Adherence means sticking to the treatment you are allocated. For example, if you are asked to take tablets as part of a trial, it’s about taking the right number of tablets at the right time, and, if appropriate, finishing the course.
Adverse events are undesired effects that may or may not be related to a treatment. For example, if you are given a drug to treat an illness and you become sick (e.g. dizziness, stomach ache or a rash), this would be described as an adverse event. If your sickness is caused by the drug, this would be called a side effect. Clinical trials will often look at both short- and long-term adverse events related to a treatment. Some adverse events may be serious and need to be reported to regulatory authorities (usually the MHRA or FDA).
All trials initiative
The AllTrials Initiative is an international movement that calls for all past and present clinical trials to be registered and their full methods and summary results reported. This increases transparency and reduces any potential ethical concerns regarding these clinical trials.
In research, the term ‘bias’ is used when a particular design or analysis is likely to favour a particular outcome. In a clinical trial, if one treatment is always given to participants who have a more severe form of a disease, then this treatment will appear worse than others. Bias can also happen if a researcher knows about the treatment a participant is receiving, and this interferes with the researcher’s ability to be impartial.
It is important to avoid bias in health research, as it can distort the results and could lead to unsafe or ineffective treatments being licensed for use, or useful treatments being overlooked. Researchers try to avoid bias by using randomisation and by ‘blinding’ those assessing the results of treatments, which may be both the patient and the doctor.
Blinding / double blinding
Blinding means that whoever is receiving or assessing the effects of treatment does not know which treatment the person has received. This helps to prevent bias. Sometimes the participant will assess the effects of treatment, sometimes the researcher will, and sometimes a researcher who is independent of the trial will carry out this assessment.
In a double blind trial, neither the participant, the doctor nor the researchers running the trial will know which treatment the participant is receiving. The aim is to avoid the hopes and expectations about the treatment, as well as the hopes and expectations of the researchers, influencing the way the benefits and risks are assessed.
It is not always possible to avoid researchers, doctors and participants knowing which treatment they are having. For example, the trial may be comparing surgery with no surgery. If the researcher knows which treatment a participant is receiving, it may be necessary for an independent researcher, who has not been involved in conducting the trial, to assess the impact of the different treatments.
Biomedical Research Centre (BRC)
The Biomedical Research Centre (BRC) is a division of the National Institute for Health Research (NIHR). The aim of the BRC is to undertake experimental and translational research in order to speed up the process of the development and implementation of new tests and treatments for improved patient benefit. Within KHP there are two BRCs: NIHR Maudsley BRC/U and Guy’s and St Thomas’ BRC.
Case Report Form (CRF)
A Case Report Form (CRF) is a printed, optical or electronic document designed to record all of the protocol-required information to be reported to the sponsor for each subject in a clinical trial. The KCTU uses an online database that utilises electronic CRFs (eCRFs) so that data can be entered directly at each study site. These eCRFs are designed according to a guidance document created by the KCTU in accordance with regulatory guidelines and trial-specific changes are implemented during the development phase.
Cell therapy unit
The Cell Therapy Unit (CTU) within KHP is the largest manufacturing facility of its kind currently built in Europe, with capacity to produce more than six final products simultaneously and a total of around one thousand therapies per year. This is a complex and sophisticated Good Manufacturing Practice (GMP) Unit built to the exacting standards required to meet the licensing requirements of the Medicines and Healthcare products Regulatory Agency (MHRA) for the manufacture of human cell and gene based therapies.
Clinical Data Management System
A Clinical Data Management System (CDMS) is a tool used to manage data in clinical research. The KCTU utilise an electronic data capture (EDC) system so that the data is stored and managed in an electronic form (InferMed MACRO).
Clinical Research Facility – KCH
The NIHR / Wellcome Trust King’s Clinical Research Facility (CRF) opened in November 2012. The build comprises of two main research areas within King’s College Hospital’s Cheyne Wing, spanning three floors with a further standalone unit. Each area has been designed and built to compliment the other in terms of ability to offer a unique and neutral space to carry out trials in a dedicated research setting.
Clinical Research Facility – GSTT
The NIHR GSTT Clinical Research Facility (CRF) has research areas on the Guy’s Campus, the St Thomas’ Campus and at the Evelina Children’s Hospital.
Clinical trials are research studies involving participants, that compare a new or different type of treatment with the best treatment currently available. They test whether the new or different treatment is safe and effective by comparing it to what already exists. No matter how promising a new treatment may appear during tests in a laboratory, it must go through clinical trials before its benefits and risks can really be known. This also applies to many different forms of treatment, such as surgery, radiotherapy, physical and behavioural interventions, not just drugs. If there is no standard treatment, the new treatment is usually compared with no treatment or with a ‘dummy’ treatment (or placebo).
Clinical Trials Unit
Clinical trials units (CTU) are specialised biomedical research units that can design, centrally coordinate and analyse clinical trials and other studies. Some CTUs specialise in different methodologies, such as randomised controlled trials, cluster randomised trials, surgical trials, and health services research. Some specialise in one disease type, whereas others are generic units. Some CTUs focus on specific phases and types of clinical trials; others conduct all phases and types of trial. Some CTU’s are accredited by the UKCRC. The only such unit across KHP is the KCTU.
CONsolidated Standards Of Reporting Trials (CONSORT)
The Consolidated Standards of Reporting Trials (CONSORT) encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomised controlled trials. The CONSORT Statement is an evidence-based minimum set of recommendations for reporting randomised trials. It offers a standard way for authors to prepare reports of trial findings, facilitating their complete and transparent reporting, and aiding their critical appraisal and interpretation. The CONSORT Statement consists of a checklist and a flow diagram: the checklist items focus on reporting how the trial was designed, analysed, and interpreted; the flow diagram displays the progress of all participants through the trial.
If you take part in a crossover trial, your treatment will change partway through the trial. For example, if a trial is comparing the effectiveness of 2 different sorts of exercise, you might take part in exercise A for the first part of the trial and then exercise B for the second, then perhaps back to A again – and so on. You cross over from one treatment group to the other, and comparisons are then made between how well you felt during the different periods. Often there will be several cross-overs in a crossover trial.
The DAMOCLES Study was commissioned by the NIHR Health Technology Assessment Programme in order to investigate the processes of monitoring accumulating trial data and to identify ways of increasing the likelihood that Data Monitoring Committees (DMCs) make good decisions. The results of the research formed a charter that describes systematically a DMC’s operating practices and procedures.
Data monitoring committee
Most trials have an independent data monitoring committee that follows the progress of the trial and makes sure it is being run properly. The people on the data monitoring committee are experts in clinical trials, statistics or in the disease being studied. They are independent of the researchers running the trial. If they think that participants are experiencing serious or unexpected side effects, or if evidence has emerged that one of the treatments being compared is clearly better than the others, they can advise that a trial is stopped.
Declaration of Helsinki
A statement of ethical principles developed by the World Medical Association to provide guidance to physicians and other participants in medical research involving human subjects.
All trials have guidelines about who can take part. These are called ‘eligibility criteria’, consisting of inclusion criteria and exclusion criteria. For example, the eligibility criteria for a trial looking at bi-polar disorder might say that the only people who can take part are people who are over 18 but under 80, and who have bi-polar disorder, but no other health problems.
Emergency Medical and Scientific (eSMS)
Emergency Medical and Scientific (eSMS) is a service provided to clinical trial management to increase the level of patient safety for participants. These services include 24/7 adverse event management and reporting, 24/7 emergency unblinding management and reporting, global centralised pharmacovigilance reporting and language and telecoms services. MEDTOX is a spin out company from GSTT NHS Trust.
An epidemiological study looks at how certain exposures (for example, an exposure may be secondary smoke or unprotected sex) or ‘risk factors’ affect health outcomes. An epidemiological study in HIV/AIDS might ask:
- How common is HIV in a particular part of the world?
- Who has HIV? (For example, do more women than men have HIV? What age are the people who have HIV?
- How did they get HIV? (For example, was it through unprotected sex? Or from their mother when she gave birth?)
An evidence base is a collection of the best available scientific research currently available about a healthcare topic, such as how well a treatment or a service works. This evidence is used by health and social care professionals to make decisions about the services that they provide and what care or treatment to offer people who use services.
Exclusion criteria determine who is not able to join a trial – for example, many trials exclude women who are pregnant, or who may become pregnant, to avoid any possible danger to a baby. Trials may also exclude people who are taking a drug that interacts with the treatment being studied. (See also eligibility criteria and inclusion criteria.)
FDA 21 CFR Part 11
FDA 21 CFR Part 11 has become a regular feature and hot topic for today’s life sciences companies. The now highly familiar abbreviation is short for “Food and Drug Administration Code of Federal Regulations Part 11 Electronic Records; Electronic Signatures”. The final 4 words really spell out what it’s all about.
These guidelines are concentrated on life science companies (e.g. Biotech, Biologic, Clinical, Contract Research Organizations, Pharmaceutical or Medical Device Organizations) on the use of electronic signatures and electronic records. Such companies need to insert controls for systems and software involved in processing electronic data that include audit trails, system validations, electronic signatures, audits, and documentation.
The guidelines then go on to define the criteria under which electronic signatures and electronic records are thought to be trustworthy, reliable and generally equivalent to handwritten signatures and paper records. The FDA states that Part 11 is applicable to all records in electronic form that are:
All documentation for any system(s) alongside other relevant records must be available for inspection by the FDA. In order to pass inspection: · Relevant detailed validation documentation needs to be in place
- Relevant standard operating procedures must be in place
- An audit history of actions needs to be maintained and secure
- Actions within the system need to be permission based
- Labels and data need to be strictly version controlled
- Signatures need to have two parts (username and password)
Of course, if you don’t want to deal with Part 11 and all its component parts, the alternative is to keep “hard paper copies” of all required records and documentation. If you choose this option, the paper documents are considered to be the authoritative document for regulatory purposes so the computer system(s) doesn’t have to meet the Part 11 requirements.
Good clinical practice
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, monitoring, recording and reporting trials that involve the participation of human participants. It is required by law in the European Union for ‘Clinical Trials of Investigational Medicinal Products’, which are a subset of clinical trials investigating the diagnostic or therapeutic properties of medicines. Information on whether a trials is a ‘CTIMP’ trial can be found at here. In all other research it is considered best practice standard.
In some clinical trials, it can be important to compare how much different treatments or treatment plans cost, as well as how well they work. This can be particularly important when two (or more) treatments are equally effective, but where one costs much more than the other.
The gathering and analysis of information about costs is called health economics. Health economic evaluation gives researchers, policymakers and those who deliver care a way to think about health benefits and costs. This enables them to try to get the best health gain for the most people, within a limited budget.
For example, economic costs involved in treating cancer include the cost of treatment, care and recovery, as well as the costs of prevention and training of healthcare personnel. Other costs include the economic costs of illness and premature death, the loss of economic productivity, decreases in the productivity of family members, and welfare and health insurance expenditure.
Inclusion criteria determine who can join a trial. For example, some trials only include people of a certain age, or at a particular stage in their illness. You may have to have a medical examination before a trial to assess whether you are suitable to take part. (See also eligibility criteria and exclusion criteria.)
Individual participant data meta-analysis is a specific type of meta-analysis where the researchers go back and look at the records for each participant who took part in every trial, instead of using summary information about groups of participants (records are anonymised so the researchers don’t know participants’ names). Then they bring these individual results together. This makes the results of the meta-analysis more reliable and enables researchers to look at how treatments have worked in different groups of participants, e.g. age group or sex.
You cannot be entered into a trial without signing a form saying that you have given your informed consent, except in extreme circumstances (for example, if you’re admitted to hospital in an emergency and you’re unconscious). If you sign this form, you are saying that you believe you have been given all the important facts about a trial, you understand them and that you have decided to take part in the trial of your own free will. Even after giving your informed consent, you are free to withdraw from the trial at any time without giving a reason and without it affecting your healthcare.
Within the context of healthcare, an intervention is something that is given to a participant as a treatment. For example, giving a drug is an intervention. Counselling and surgery are also interventions.
Within the context of a clinical trial, the ‘intervention arm’ is the name given to the group of people receiving the new treatment or treatment plan.
Investigational Medicinal Product (IMP)
Investigational Medicinal Product (IMP) is a term used by regulatory agencies to describe a trial drug used in a clinical trial.
King’s Clinical Trials Unit (KCTU)
The King’s Clinical Trials Unit (KCTU) is the only UKCRC accredited Clinical Trials Unit across KHP and provides academic collaboration and/or service support to academic led clinical trials.
King’s Health Partners (KHP)
The King’s Health Partners (KHP) is one of only six Academic Health Science Centres in England designated by the Department of Health. The partnership brings together world-leading research at King’s College London and three successful NHS Foundation Trusts (Guy’s and St. Thomas’, King’s College Hospital and South London and Maudsley). The aim of KHP is to create a centre where world-class research, education and clinical practice are brought together for the benefit of patients.
King’s Health Partners Clinical Trials Office (KHP-CTO)
King’s Health Partners Clinical Trials Office (KHP-CTO) was set up as a joint initiative between King’s College London, Guy’s and St Thomas’ NHS Foundation Trust, King’s College Hospital NHS Foundation Trust and the South London and Maudsley NHS Foundation Trust to formalise the pre-existing collaborations between the partners, to develop their clinical trials potential and to increase the quality and delivery of clinical trials. The CTO has two sections: the Commercial Team which provides a single interface for those wishing to conduct trials sponsored by the pharmaceutical and allied healthcare industries; and the Quality Team that supports investigators at King’s Health Partners institutions who undertake clinical trials where King’s Health Partners are sponsor or co-sponsor to ensure delivery of the statutory obligation contingent on sponsorship of trials.
Mental Health Biomedical Research Centre (MHBRC)
This refers to the Mental Health branch of the Biomedical Research Centre (MH-BRC – see BRC). The focus of this unit is on individualised treatments for those with mental ill health.
A meta-analysis involves a researcher bringing together the numerical results of all previous research (usually randomised trials) about one particular treatment or plan.
A meta-analysis can be important because it allows us to pick up small differences between treatments. These differences can be very hard to spot, so trials need to include large numbers of participants to pick these up. Many trials are not big enough, so we cannot be sure whether any differences that we find are because of real differences between the treatments or just due to chance. By bringing together the results of all trials of a particular treatment in a meta-analysis, we can look at the experience of more participants than in a single trial. This gives a more reliable and accurate measurement of the effect of the treatment and the best way of seeing which treatments are best.
Methodological research in relation to clinical trials is research looking at ways to improve the how trials are designed, carried out, conducted, analysed, interpreted and reported.
ModePharma is a private company which provides medication and associated services to clinical trials, with a particular focus on academic led trials. They may be contracted for the manufacturing and packaging of clinical supplies, including: placebo manufacture and blinding, pharmaceutical development, bulk manufacturing of IMPs, packaging and labelling, monitored storage, and distribution and shipments.
National Health Service Research and Development (NHS R&D) oversees the development and management of many research studies. The group provides advice, training and support to clinical trials units and sponsors regarding the most appropriate actions at any given stage of clinical trial development and conduct.
The National Institute for Health Research (NIHR) is a health research system funded by the Department of Health to improve the health and wealth of the population through research. The NIHR provides substantial funding for many clinical trials so that important medical research can be undertaken.
In an observational or epidemiological study, researchers do not offer different treatments as part of the research. They study how certain ‘risk factors’ and disease outcomes are related.
The term ‘open trial’ may refer to:
- A trial that is still recruiting people or following them up. When a trial is closed, it stops recruiting people and following them up. The researchers collect and analyse the results, ready for publication
- A trial where the researcher and the participant know which treatment they are receiving – they are not blinded (see blinding). This is usually called an ‘open label’ trial
Open label trials
In an open label trial, both you and your doctor will know which treatment you are receiving. This is the opposite of a double-blind trial (see blinding).
Outcomes are changes in a participant’s health state. For example an outcome might be that your blood pressure is reduced as a result of taking tablets prescribed by the doctor. Outcome measures are used to measure the effects of a treatment. They might include physical measurements – for example measuring blood pressure, or psychological measurements – for example measuring people’s sense of well-being. If someone takes part in research, they may be asked questions, or may be asked to have extra tests to assess how well the treatment or service has worked.
Phases of drug trials
- Phase I: relates to the safety of the drug under investigation in healthy volunteers. The aim is to establish the appropriate doses of a drug to be investigated in later trials and understand how the drug is dealt with in the body.
- Phase IIa: Phase IIa trials are similar to Phase I studies but aim to link to Phase II by capturing data more typically associated with a straight Phase II trial.
- Phase II/IIb: usually involves a small (usually randomised) trial investigating the potential benefits of a drug among patients with a particular disease. These trials are also used to establish which therapies have the potential to be investigated in full-scale, Phase III randomised trials.
- Phase III: these trials are full-scale randomised controlled trials evaluating the benefits of a drug against a placebo or standard therapy in a substantial number of patients. This is the key stage in establishing the impact of a drug.
- Phase IV: relates to the stage after a drug has been approved and involves the long-term monitoring of the safety of the drug. It sometimes refers to the marketing process by which the drug is brought to the attention of a large number of medical practitioners.
A placebo is a dummy treatment that is designed to be harmless and to have no effect. It looks, smells and tastes like the treatment being tested, so that people don’t know if they are taking the dummy treatment or the treatment being tested (see blinding). It allows researchers to test whether a new intervention has any benefit other than a psychological response, where people feel better because they have received a treatment. This response is called the ‘placebo effect’. By comparing people’s responses to the placebo and to the treatment being tested, researchers can tell whether the treatment is having any real benefit.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. The aim of the PRISMA Statement is to assist authors to improve the reporting of systematic reviews and meta-analyses. The PRISMA Statement is comprised of a checklist and flow diagram.
A protocol is the plan for a piece of research. All protocols for clinical trials need to be approved by an ethics committee. A protocol usually includes information about:
- What question the research is asking and its importance/relevance
- The background and context of the research, including what other research has been done before
- How many people will be involved
- Who can take part
- The research method
- What will happen to the results and how they will be publicised
A protocol describes in great detail what the researchers will do during the research. Usually, it cannot be changed without going back to a research ethics committee for approval.
Quality Control in trials are the steps taken during the trial to ensure that the trial meets protocol and procedural requirements and is reproducible.
Quality of life
As well as measuring the physical effects of a treatment (for example changes to blood pressure), many trials now try to assess the impact of treatments on people’s quality of life. For example, a ‘quality of life’ study might ask about:
- Your mood and general sense of well-being
- Whether you feel more tired than usual
- Whether you are managing to do more things than before
- Whether your sleep patterns have changed
If you take part in a randomised controlled trial, you will have an equal chance of receiving any of the treatments being compared. The decision about which treatment you’ll receive is based on chance. A computer will decide which treatment you’ll receive, not you or the doctor. This is called randomisation.
Randomisation ensures that the groups of people receiving different treatments in a trial are as similar as possible, except for the treatment they receive. This is important because it means that researchers can be sure that any differences between the groups are only due to the treatment.
Randomisation is the best way of ensuring that the results of trials are not biased. For example, if a doctor chose which treatment a participant should receive as part of a trial, she or he might give the new treatment to sicker participants, or to younger participants. This would make the results of a trial unreliable. Randomisation helps prevent this kind of bias.
Randomised controlled trials
Many clinical trials are randomised controlled trials (RCTs). Clinical trials aim to make a fair comparison between a new treatment and the current treatment on offer, or between two (or more) existing treatments, to see which one works best.
A controlled trial compares two groups of people: an experimental group who receive the new treatment, and a control group who receive the usual treatment or a placebo. The control group allows the researchers to see whether the treatment they are testing is any more or less effective than the usual or standard treatment.
If you take part in a randomised controlled trial, you will have an equal chance of receiving any of the treatments being compared. The decision about which treatment you’ll receive is random – or based on chance. A computer will decide which treatment you’ll receive, not you or the doctor. This is called randomisation.
Randomisation ensures that the two groups of people in a trial are as similar as possible, except for the treatment they receive. This is important because it means that researchers can be sure that any differences between the groups are only due to the treatment.
Randomisation is also the best way of ensuring that the results of trials are not biased. For example, if a doctor chose which treatment a participant should receive as part of a trial, she or he might give the new treatment to sicker participants, or to younger participants. This would make the results of a trial unreliable. Randomisation helps prevent this kind of bias.
Serious Adverse Event
A serious adverse event (SAE) is any adverse event or adverse reaction that results in death, is life-threatening*, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect or.
Medical judgement should be exercised in deciding whether an adverse event/reaction should be classified as serious in other situations. Important adverse events/reactions that are not immediately life-threatening or do not result in death or hospitalisation, but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious.
* Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it were more severe.
Side effects are undesired effects that are related to a treatment. For example, if you are given a drug to treat an illness and it makes you sick (e.g. dizziness, stomach ache or a rash), this would be described as a side effect. Clinical trials will often look at short- and long-term side effects related to a treatment. Some side effects may be serious and need to be reported to regulatory authorities (usually the MHRA or FDA).
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 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.
An individual, company, institution, or organisation that takes responsibility for the initiation, management, and/or financing of a clinical trial.
Systematic reviews aim to bring together the results of all studies that have been carried out around the world addressing a particular research question. They provide a comprehensive and unbiased summary of the research.
For example, one clinical trial may not give a clear answer about the effectiveness of a treatment. This might be because the difference between the treatments being tested was very small, or because only a small number of people took part in the trial. So systematic reviews are used to bring the results of a number of similar trials together, to piece together and assess the quality of all of the evidence. Combining the results from a number of trials may give a clearer picture. When researchers combine the numerical results of these trials and compare them, this is called a meta-analysis.
Template for Intervention Description and Replication (TIDieR)
The Template for Intervention Description and Replication (TIDieR) is a checklist that outlines information to include when describing an intervention and the location of the information. The focus of TIDieR is on reporting details of the intervention elements of a study. Other elements and methodological features of studies are covered by other reporting statement and checklists.
The Clinical Trials Toolkit (Clinical Trials, Data and Tissue, Experimental Medicine, Stem Cells) provides practical advice to researchers in designing and conducting publicly funded clinical trials in the UK. Through the use of an interactive routemap, the Toolkit provides information on best practice and outlines the current legal and practical requirements for conducting clinical trials. See www.ct-toolkit.ac.uk. There are additional toolkits for data and tissue www.dt-toolkit.ac.uk, experimental medicine www.em-toolkit.ac.uk and stem cells www.sc-toolkit.ac.uk
The UK Clinical Research Collaboration (UKCRC) is an organisation to establish the UK as a world leader in clinical research. The UKCRC provides a forum that enables all Partners to work together and promotes a strategic approach to the identification of opportunities and obstacles to clinical research and their resolution.