Experimental medicine (EM) is a broad term and has no legal definition in the UK. The guidance given on this page is based on the following understanding of the term as it is found on the MRC website, and we comment on how it relates to the regulatory landscape.
EM is undertaken in human participants to gain an understanding of diseases or to test a new treatment. It can inform the design of later phase clinical studies. Examples of such studies may be novel readouts or technologies related to early evaluation of clinical efficacy or proof-of-concept studies. Some EM studies may be regulated as clinical trials (CTIMPs), if testing the safety or efficacy of a medicine, some may be legally classed as medical device or in vitro diagnostic devices studies. As such, the regulatory requirements for EM differ. We provide legal definitions (for CTIMPs, medical devices or in vitro diagnostic medical devices) to help you understand when legal requirements apply, and signpost further information. This section focuses on EM studies which are not within scope of the legal definitions. These EM studies should be managed according to local university, NHS policy and professional codes of conduct.
While we have applied the information within this section to EM studies, robust risk management is vital for any study. If your study is a CTIMP, or clinical investigation of a medical device there would be additional risk management requirements.
Wider policy landscape for EM studies
Understanding health research gives a good introduction to the landscape, relevant for EM as well as other health research.
All EM studies involving human participants should be conducted in accordance with the principles of good clinical practice (GCP). Much of the detailed guidance contained within GCP can be difficult to relate directly to academic-led, small scale, interventional studies; however the principles of GCP are relevant to all research involving human participants. The Health Research Authority (HRA) has a good introduction to GCP with a link to the International Conference on Harmonisation GCP Guideline (ICH GCP). Not all ICH GCP principles will apply to EM studies.
HRA and MHRA have issued a joint statement regarding the application of GCP training to researchers. About two thirds down the page you will also find guidance on research studies which are not CTIMPs.
All EM studies conducted within the NHS or social care should comply with the UK policy framework for health and social care research.
MRC has put together a page with good research practice policies and guidance.
Any EM study which involves human participants will need review and approval from a research ethics committee before the study can commence. You will find information on this topic in ethical approval.
Guidance on conducting international research studies is available from the MRC guidelines for management of global health trials and the Nuffield Council on Bioethics: research in developing countries.
Register trials
Any MRC-funded interventional trial, clinical or public health study with a study design that is within the scope of MRC policy on open research data from clinical trials and public health intervention studies must register with the International Standard Randomised Controlled Trial Number (ISRCTN).
The ISRCTN registry is recognised by both the International Committee of Medical Journal Editors (ICMJE) and the World Health Organization. ISRCTN gives each trial a unique number which then enables tracking of the study through publications and reports. The ICMJE require all randomised controlled trials to be registered with an approved scheme before allowing publication of trial findings. If your study has not been submitted to an approved registry, you may not be able to publish your findings. There is a fee for registration with ISRCTN, and you should request funding for registration in your grant application.
Risk management
In order to fully develop your research protocol or proposal, you should define the nature and extent of any benefits likely to be achieved while ensuring the following risks are minimised:
- the safety of potential participants
- the rights and dignity of participants
- the environment and wider community
- the successful completion of the study
- the credibility of the data collected
- the safety and wellbeing of the research team
The assessment of potential risk should be based on published data and your own experience. Early consideration of risk will facilitate your application for relevant approvals later on.
Identified risks can be minimised by implementing appropriate management and monitoring strategies. Determining what is an acceptable level of risk is subjective. In general risks should not outweigh benefits (Declaration of Helsinki). Research that is unlikely to offer participants direct, personal benefit should only pose minimal risk of harm. Minimal risk of harm should be a consensus judgement, informed by guidelines, the experience of Investigators and their peers, participants themselves and research ethics committees. If it is possible to obtain similar information by a different and less risky methodology, the alternative approach must always be considered.
Consultation with research ethics committees, research and development offices and other relevant regulators will determine whether your protocol or proposal is appropriate, or whether you should consider using a different, less risky approach to address your research question.
Identifying risks to safety
Specific safety considerations are largely dependent on the nature of the proposed intervention. Risks to participant safety should be considered on a case-by-case basis. Aspects you should consider as part of your safety assessment include properties of any interventional agent (drug, chemical or biological agent, or medical device) to determine the potential mechanism by which it could represent a hazard to human health. Also, determine the likelihood that, in the event of exposure (deliberate or otherwise) the agent could actually cause harm to human health and the severity of this potential harm. You should also have an understanding of the nature of the work to be undertaken and review in detail what control measures need to be in place to safeguard human health.
Detailing predicted adverse events in your protocol or proposal will also limit the need for expedited reporting of these events once your study is ongoing.
A useful document is the European Medicines Agency (EMA) scientific guidelines for the non-clinical safety data required to support human clinical trials of new pharmaceuticals. This guidance is directed to those proposing early phase CTIMPs however some of the guidance may be more generally applicable.
The Academy for Medical Sciences (AMS) has published microbial challenge studies of human volunteers (PDF, 227KB) that addresses the risks, benefits and conduct of microbial challenge studies of human volunteers, with particular emphasis on vaccine development. Although directed specifically at best practice in microbial challenge studies, most of the findings can be applied more generally to EM studies.
Quality of interventional agent
Central to the safety of chemical or biological agents is the quality of their manufacture, their purity and characterisation. Whenever practicable all agents should be manufactured to good manufacturing practice (GMP) standards (or equivalent, for example Food and Drug Administration standards). All medicines available on the market in GB, the EU and US should comply with these standards.
Be aware that any investigational medicinal product (IMP) to be used in a clinical trial under the UK Medicines for Human Use (Clinical Trials) Regulations (including placebos) must be manufactured to GMP standards. This includes all test compounds or medicines (including placebos) to be used in phase one, safety trials or proof of concept trials. Challenge agents and supporting medication used in some CTIMPs (meaning agents or medication that are not being used as an IMP) are not required to be manufactured to GMP standards. If they are not, investigators must be able to justify their standard of manufacture (see ‘Non GMP agents’).
It may not always be deemed necessary or practical to ensure all agents used in other research studies (meaning non-clinical trials of investigational medicinal products) are manufactured to GMP standards. However, investigators must be able to justify the standard of manufacture of the proposed interventional agent, and appropriate safety monitoring and management strategies should be implemented.
EMA guidance on the quality of medicines is directed to those planning clinical trials of investigational medicinal products (CTIMPs), but some of guidance will be more generally applicable.
There are also findings in the Expert Group on Phase One Clinical Trials: final report (an independent report about the TGN412 clinical trial) which are applicable to all small-scale interventional studies.
Non GMP agents
For agents where it is not practicable to obtain and use a product manufactured to GMP, the following quality control issues should be taken into account, considering the potential risks posed by the intervention:
- previous clinical experience of using the agent
- pharmacology
- toxicology
- facilities and likely consistency of manufacturing process
- purity and contaminant testing
- batch comparisons
- handling and formulation requirements
- storage conditions, duration of storage and stability
The use of agents not manufactured to GMP, or equivalent standards, must be monitored and managed accordingly if their use is to be justified.
Hazards of assessments methods
The specific considerations to be made when establishing the potential hazards of proposed assessment methods are largely dependent on the nature of the assessment method: each method should be considered separately. You should consider the following points in your assessment:
- the nature of any proposed assessment methods to determine the potential mechanism by which they could represent a hazard to human health
- the likelihood that assessment methods could actually cause harm to human health and the severity of this potential harm
- the risk that the proposed assessments may uncover information about the participants’ health of which they were unaware. You can find guidance about this in the framework on the feedback of health related findings in research
- the nature of the work to be undertaken and a detailed review of the control measures to safeguard human health and to handle sensitive health information
Be aware that the risks of using assessment methods involving ionising radiation in research are governed by law. You can find further guidance on ‘approvals for clinical trials’ in clinical trials of investigational medicines and advanced therapies.
Hazards to researchers (health and safety)
While it is crucial to consider the safety of all participants in a study, do not forget to consider any hazards which you and your research team may be exposed to. You should consider the following aspects:
- will your research team be working within an environment or a community which may pose a threat to their personal safety?
- will your research team be using hazardous compounds or other potentially hazardous agents?
- are you, and your research team fully aware of all health and safety implications of the proposed study?
- are you, and your research team likely to have appropriate indemnity in place from either your employer or another organisation? The Health Research Authority (HRA) has guidance on indemnity cover for NHS staff delivering research and we provide information on indemnity for MRC institutes
Employing organisations have statutory responsibilities for ensuring that their employees are offered adequate protection against any harm they may encounter while doing their job. Appropriate staff induction training and early consultation with employers or research host organisations is essential to manage these risks.
Hazards to wider community
Some interventions may, by their nature, potentially pose a hazard to the wider community or environment; you will want to consider a variety of aspects of your study:
- the properties of any interventional agent to determine the potential mechanism by which it could represent a hazard to the wider community or environment
- the likelihood that, in the event of exposure (deliberate or otherwise) the agent could actually cause harm to the wider community or environment, and the severity of this potential harm
- the nature of the work to be undertaken and a detailed review of the control measures to safeguard the health of the wider community or environment
In some specific circumstances investigators should also consider the potential for inappropriate and potentially harmful use of agents (microorganisms or other agents) used for research purposes such as ‘dual-use’ of research agents or research findings. MRC has issued a joint policy statement with the Biotechnology and Biological Sciences Research Council and the Wellcome Trust on managing the risk of research misuse.
Minimising safety risks
Many of the safety issues you identify can be effectively managed (by the implementation of appropriate control measures to safeguard the safety of participants), thereby minimising the risk they pose. The following are some strategies you should consider in light of the intervention and assessment methods proposed:
- training and expertise required of all staff involved in the study (induction training, general clinical or research training or expertise and study specific training)
- facilities required to conduct the proposed study, and deal with adverse outcomes
- application of exclusion criteria to recruitment and implementation of appropriate screening to support these
- ensuring appropriate procedures are in place to manage any risks posed to participants (or others) at the end of their involvement in the study
- assuring the quality of the interventional agent
- good communication with all members of the research team
- appropriate levels of containment or quarantine and ensuring compliance with these
Safety monitoring
Safety monitoring is essential if you are to manage outstanding risks. Appropriate monitoring will enable the research team to identify when a safety issue has occurred; which may in some circumstances, necessitate intensive observation of participants.
When an issue has occurred, effect monitoring will enable appropriate action to be taken to minimise the impact of such a safety issue; this could involve ensuring appropriate NHS facilities are available if required.
It is important that your research team are made aware of any adverse outcomes and any actions arising from such outcomes. When appropriate, the wider research community should also be made aware of any lessons that have been learned.
The intensity and focus of safety monitoring should be based on the risks to participant safety inherent in the protocol or proposal, which will vary from study to study.
You should ensure contingency arrangements are made for dealing with predicted adverse events. You should consider the need for independence in safety monitoring and in making any safety decisions. Some of the systems employed in large scale clinical trials will not always be appropriate for small scale, academic led, interventional studies.
Reports of serious adverse events
Any serious adverse events, which you believe may be related to participation in the study, and which were not ‘expected’ (meaning not predicted as potential adverse outcomes in the original protocol) must be reported to the main NHS Research Ethics Committee within 15 days of you becoming aware of the event.
Progress reporting
HRA ask for annual reports to be submitted to the main REC on the anniversary of the original favourable ethical opinion. Funders and sponsors may also require progress reports. HRA has further guidance on progress reporting.
Reports should include any safety issues encountered
You can find more information on HRA guidance on safety reporting. This covers guidance for all studies and has a specific section at the bottom for non-CTIMP studies.
Audit
Funders, sponsors and NHS or university research and development offices may wish to conduct an audit of your study, in order to fulfil their responsibilities under the UK policy framework for health and social care research. The extent, scope and frequency of audits will vary between organisations, and should be determined by the risks the study is believed to pose to the organisation. Possible elements of an audit could include:
- adherence to protocol and other study documentation
- evidence of monitoring and reporting
- recruitment and consent procedures
- quality assurance of data which could involve source data verification
CTIMPs, and other studies regulated by a competent authority, may also be subject to inspection. For further information on audits and MHRA inspections please visit Clinical Trials Toolkit: Audit and Clinical Trials Toolkit: MHRA inspection.
Depending on the precise nature of your study, you also need to be prepared for a Human Tissue Authority (HTA) or a Home Office inspection.
Identifying general risks
When developing a study protocol or proposal risks beyond those associated with participants’ safety should be considered, such as risks to:
- participant recruitment
- data validity and integrity
- staffing and resources
Participant recruitment
Successful completion of your study will depend on:
- recruiting an appropriate number of participants to ensure you can adequately address the study objectives
- involving only those participants who fall within the designated inclusion criteria and
- ensuring you can collect full or sufficient datasets from participants (including any longer term follow up data)
In considering the risks to participant recruitment, you should make practical judgements that are based on experience of working with the study population, together with the complexity and intensity of the protocol.
Data validity and integrity
To ensure that your study provides good quality data, you need to consider not only the quality of the protocol but also how the protocol is followed and how data is collected. You should consider the following aspects:
- are there any reasons why your protocol, or parts of your protocol may be difficult to follow by the research team?
- how robust is your randomisation procedure (if you are employing one)?
- are the proposed outcome measures valid, reproducible and objective?
- how robust or complex is the methodology used to document and collate data collected from participants?
- must all your participants be fully compliant with the protocol?
- do you need to consider guarding against research fraud?
Providing specific training and support to all those collecting data can help guard against many data quality issues.
Staffing and resources
Chief investigators must ensure that all members of the research team have read and understood the protocol, the roles they are being asked to undertake, and any relevant safety information, before the research activity begins. Failure to do so not only potentially compromises the safety of participants, but also the integrity of the data collected. Speak to your sponsor and all involved departments to determine what resources you will need and whether you have sufficient funding to cover all costs. MRC has a page describing all costs we fund.
Monitoring of general risks
Risk proportionate management and monitoring strategies should be implemented, informed by the outcome of a formal risk assessment. Management strategies designed for later phase clinical trials are not always appropriate for small scale studies. However, it is vital that an appropriate level of delegation is implemented and that communication is maintained between decision makers and the rest of the research team; this may include staff who are not directly employed to work on the study such as collaborators. Independence in decision making should be considered but may not be deemed necessary where the risks are low. You should also consider what skills are required to aid decision-making, for example statistical input may be helpful in some circumstances, but not all. You can find more information on who to consult and what a statistician can offer in your local research office.
Any outstanding risks to participant safety or more general risks should be actively monitored. The intensity and frequency of monitoring, whether it be monitoring of participants’ health, monitoring recruitment and consent or monitoring data quality and protocol adherence, will be determined by the risks involved. The outcomes of monitoring must inform ongoing risk assessment as research progresses. Re-assessment of risk may identify the need to amend the protocol or to make urgent safety measures.
Monitoring will identify if any of the predicted risks (or others) become a reality (meaning the risk management processes put in place are sufficient and appropriate). Additionally, monitoring will ensure that the risk management processes devised are being fully implemented.
The intensity and focus of monitoring should be risk-based and will vary from study to study.
Areas you should consider monitoring are:
- recruitment and consent processes: for example monitoring the level of understanding of participants, or simply conducting a check that all those recruited have given their written consent in the prescribed manner
- accrual rates and progress of study: ensuring recruitment is on track
- protocol or proposal adherence: by the research team and participants
- data collation and handling: missing data, data entry errors, invalid data; achieved by processes like applying validation rules to data fields or conducting source data verification
Your study may also be subject to external audit by your study sponsor. Such an audit may include examination of your internal quality assurance processes.
You should consider the need for independence in monitoring whenever the level of risk suggests this is appropriate.
Amendments
In light of emerging data and ongoing risk assessment, it may be necessary to make changes to the protocol or to other study documentation (such as participant information sheets). It is good practice to use a version numbering system or ‘version control’ on all study documentation, so that you and your research team are able to ensure that you are working from the correct documents. Any amendment must be effectively communicated to the research team and collaborators, including the date of implementation.
The HRA has further guidance for amendments.