Clinical Research Methodology

Types of Study

A case–control study is a retrospective study (collection of data from past events) investigating the relationship between a risk factor and one or more outcomes. People with a predefined risk factor or outcome are selected (cases) and compared with people who do not have these factors (controls). A case–control study primarily aims to investigate cause and effect. Generally speaking, prospective studies will reduce bias, as the research question is predefined, and then evaluated.

A cohort study is a prospective, observational study looking at a specific effect of a treatment or risk factor over a period of time.

Systematic research is the process whereby a project is based on an agreed set of rules and processes (protocol) and these are rigorously adhered to. It is against this protocol that the research is evaluated. This will reduce bias, as predefined rules are adhered to, and selecting significant findings of interest from numerous variables that could occur by chance is avoided.

Qualitative research is research undertaken in the field (natural settings) and usually analysed by non-statistical methods.

Quantitative research involves measurements and analysis of observations using statistical methods.

Surveys are based on a representative sample of a population being questioned at one time point.

Randomised controlled trials (RCTs) are viewed as the ‘gold standard’ for evaluating health services effectiveness and interventions in relation to specific conditions. Participants are randomly allocated to two or more groups, and direct comparisons can be made between the groups. The only difference between the groups should be the investigation intervention. Therefore, any differences found between the groups should be attributable only to the intervention, and a causal relationship is far more likely (rather than association).

Cluster randomised trials (CRTs) differ from RCTs in that the unit of randomisation is not the individual participant but something else, for example a ward, a department or a service provider. CRTs are particularly useful when testing differences in a method or approach to patient care or evaluating a new standard of care or other practice-wide, hospital-wide or system-wide change that impacts patient outcomes. Randomising at the cluster level as opposed to individual patients reduces the potential for contamination because all patients within the cluster are highly likely to receive the same treatment or care, and thereby have similar outcomes. Thereby, this is an effective method to test an intervention by some clusters randomised to using it in practice and others not using it at all. The number of clusters will be dependent on cluster size and outcomes, but typically a minimum of eight clusters is required.

Stepped wedge cluster randomised trial is a pragmatic study design increasingly popular for evaluating service delivery type interventions. In a stepped wedge study design, more clusters are exposed to the intervention towards the end of the study than at the start. In the initial study phase, none of the clusters are exposed to the intervention. At regular intervals (steps) one cluster (or group of clusters) is randomised to introduce the intervention, until all clusters are using it; there is then a period when all clusters are exposed to the intervention. Continuous data collection throughout the study period means all clusters contribute to both the control and intervention phases.

What is Audit?

Audit is not research. The differences are outlined in Table 15.1 . Clinical audit is a quality improvement process that seeks to improve patient care and outcome. This is achieved through systematic review of care against explicit criteria and the implementation of change. Aspects of the structure, processes and outcomes of care are selected and systematically evaluated against explicit criteria ( Fig. 15.1 ). Where indicated, changes are implemented at an individual, team or service level and further monitoring is used to confirm improvement in healthcare delivery ( definition endorsed by the National Institute for Clinical Excellence , ). In short, audit is the process used by health professionals to assess, evaluate and improve care of patients in a systematic way in order to enhance their health and quality of life ( ).

Audit does not require ethical committee review or approval, nor is it under the same regulatory requirements as research. Most hospital trusts will have a robust infrastructure that deals with clinical audit, including registration of projects, which has become an integral part of clinical practice.

Integrated Research Application System

The European Union (EU) Directive says ‘Member States shall take the measures necessary for the establishment and operation of Ethics Committees’. The responsibilities of the ethics committee are to safeguard the rights and wellbeing of trial subjects, and to ensure proposals meet the requisite standards. It is unlikely that this EU Directive changes for studies in the UK in light of Brexit.

It is stipulated that there must be at least seven members of an ethics committee, including scientific/expert and lay representatives. Research ethics committees (REC) can be either Main or Local (MREC/LREC), depending on their size and the experience of their members. All clinical trials of a medicinal product and multicentre studies need to be ethically reviewed and approved by a Main REC, following which, Local REC approval is granted for Site Specific Information (SSI). Every study should have a chief investigator (CI) and each site must have a local principal investigator (PI), who has overall local responsibility for the trial or study. The ethics committee assesses the suitability of the local PI and support staff in addition to the appropriateness of the local research environment.

An electronic application form ( www.myresearchproject.org.uk ) must be used for applications in the UK. This consists of three parts: part A gives general details of the research project, part B involves information on specialised topics, including the use of existing or newly obtained biological specimens and part C is SSI (local assessor). A separate (duplicate) application form can be accessed on the Integrated Research Application System (IRAS) website for R&D approval (see below). Once completed, with the requisite signatures, both forms can be processed through the R&D department for the participating Trust or PCT.

Once logged in, the form can be edited any number of times by the individual with the pass code and can be electronically transferred to collaborators for comments and editing.

When complete, details of how to make your booking for ethical review can be found on the ‘e-submission’ tab of the form you wish to submit. This provides step-by-step instructions and a direct link to the booking portal. When you book make sure you have your application available as you will need to answer questions to determine which RECs are suitable to review your study. This is dependent on the study type and population, for example some committees focus on patient groups, paediatrics for example. The form can then be locked and submitted online and one paper copy, with requisite signatures accompanied by the study protocol, including patient information and informed consent forms, should be delivered to the ethics committee administrator. The administrator will check all the paperwork is present and then send confirmation of receipt of the application. For single-centre studies, parts A and B of the form need to be completed. If the study is undertaken in more than one institution/hospital, SSI will need to be sought in all additional centres. The letter of receipt gives details as to how to ensure this process happens concurrently with MREC consideration.

RECs meet frequently, and the date when the application will be discussed will be notified to the applicant. Each committee will only review a certain number of proposals at each meeting, and an applicant can choose an appropriate committee, according to their commitments and time schedule. A local committee will not therefore always review research from its own institution. A multicentre study (three or more centres) will require a Main REC. Attendance by applicants is not mandatory, but applicants can be invited to attend to clarify any ambiguous or difficult ethical issues. The REC can ask for alteration or clarification of the application on one occasion – at this point the clock stops, and any delay is entirely the responsibility of the applicant. Apart from this delay, a decision will be given within 60 days.

Research and Development Approval

All projects involving NHS patients, staff or services require approval from the local research and development committee. The form is available online and interconnects with the ethics forms. This needs to be completed at every participating centre, including single-centre sites and academic projects. Most research and development committees expect an early application. Advice is available from your local Research and Development or Research and Development Support Unit (RDSU).

International Conference on Harmonisation Guideline on Good Clinical Practice

This document sets out an internationally agreed quality standard for designing, conducting, recording and reporting trials involving human participants. This ensures unified standards of research in the EU, but also covers Japan and the United States. Good clinical practice guidelines from Australia, Canada, the Nordic countries and the World Health Organization (WHO) were also considered in the preparation of these guidelines. The principles of the International Conference on Harmonisation Guideline on Good Clinical Practice (ICH GCP) originate from the Declaration of Helsinki (1964) last updated in 2000. Accordance gives assurance to the public that the rights and wellbeing of the subjects is protected, and that trial data are credible. Information can be found at www.ich.org .

The European Union Clinical Trials Directive

The EU Clinical Trials Directive (2001/20/EC) is the legislative framework that implements ICH GCP in the EU and also in Iceland, Norway and Liechtenstein, which form the European Economic Area (EEA). The aims of this Directive are three-fold:

• 1.

  To protect the rights, safety and wellbeing of trial participants

• 2.

  To establish transparent procedures that will harmonise trial conduct in the EU and ensure the credibility of results

• 3.

  To simplify and harmonise administrative provisions governing clinical trials.

The original clinical trials regulations were superseded by the Clinical Trial Regulation (Regulation (EU) No 536/2014). The aim of this Regulation is harmonisation in the assessment and supervision processes for clinical trials throughout the EU, via the Clinical Trials Information System (CTIS). This will provide a centralised EU portal and database for all clinical trials under the jurisdiction of the Regulation. Although the Clinical Trials Regulation was adopted and came into force in 2014, the timing of its application is reliant on confirmation of the full functionality of the CTIS, which will involve an independent audit. This was scheduled for December 2020 but has been postponed due to the global COVID-19 pandemic. Updates are available on the European Medicines Agency website ( www.ema.europa.eu ).

Key benefits of the updated Regulation are to create a favourable environment to undertake clinical trials, in the EU developing and maintaining high safety standards for participants and transparency of trial information, thereby necessitating consistent rules for conducting clinical trials throughout the EU and publicly available information regarding the authorisation, conduct and results of each clinical trial undertaken in the UK. The key benefits of the Regulation include:

• Harmonised electronic submission and assessment processes for clinical trials conducted in multiple Member States

• Improved collaboration, information-sharing and decision making between and within Member States

• Increased transparency of information on clinical trials

• Highest standards of safety for all participants in EU clinical trials ( ).

The UK Government has confirmed it is committed to implementing the EU Clinical Trials Regulation 534/2014 into UK law post-Brexit and this is referred to in the MHRA Five Year Plan 2018–2023 (MHRA, 2021).

Investigational Medicinal Products

The regulations cover all clinical research on ‘investigational medicinal products (IMPs) for human use’ (excluding non-interventional trials, see below). The Regulation (EU) No 536/2014 Article 2(5) defines an IMP as ‘a medicinal product which is being tested or used as a reference, including as a placebo, in a clinical trial’. This includes products already with a marketing authorisation but which are used or assembled differently from the authorised form, or to gain further information regarding an authorised form. The regulations are required when the trial is designed to support a medical claim, and when the IMP will influence (treat or prevent) a disease process.

Auxillary Medicinal Products

This is defined as ‘a medicinal product used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product’. So, an Auxillary Medicinal Product (AMP) would be required when a protocol requires the use of a medicinal product as a challenge agent, a rescue medication or background treatment. Note that AMPs are defined as medicinal products, therefore not all products need to be recorded as such. Additionally, concomitant medications do not fall into this category.

Medical Devices

A medical device is not recognised as an IMP, that is, this is when the principal intended action of an intervention in a trial is fulfilled by physical means (device), not pharmacological, immunological or metabolic means (medicinal product). However, medicinal devices may be assisted in their function by a medicinal product (e.g. intrauterine contraceptive (device) with progestogen (medicinal product)), and under these circumstances will require conformity to these regulations.

Although there is no legislative requirement to follow the exact requirements of ICH GCP when an IMP is not investigated (e.g. in a trial of a surgical procedure), it remains good practice to follow the same basic principles, although reporting requirements to the MHRA may not be mandatory (see below).

A practical implementation of the ICH GCP guidelines can be found in Table 15.2 .

Responsibilities of an Investigator

The chief investigator (CI) must adhere to the 13 principles of GCP (see Table 15.2 ). In addition, according to ICH CGP the investigator must, by education, training and experience be qualified to fulfil this role, as evidenced through an up-to-date CV or other documentation. They must facilitate monitoring and auditing of the study by the sponsor and inspection by the regulatory authorities. They must maintain a list of the individuals to whom significant trial-related duties have been delegated, demonstrating appropriate qualifications for their relevant tasks.

The investigator must show that recruitment in the agreed timeframe is realistic. They are responsible for ensuring that there is sufficient time to undertake the project, and there is adequate staffing to execute the study. This includes guaranteeing that all staff employed will be adequately trained to undertake the responsibilities expected of them during the study. They also should examine the reason a subject withdraws from a trial prematurely and communicate all significant matters with the ethics committee. They must ensure compliance with the trial protocol. They should be knowledgeable about all aspects of the investigational project and have responsibility for it. This includes responsibility for randomisation procedures and unblinding policies where necessary, as well as for obtaining informed consent from all trial participants. All trial-related medical decisions are the responsibility of a qualified medical practitioner. Attending clinicians should be aware of a participant’s involvement in a trial.

The investigator also has responsibilities regarding records and reports. They have overall responsibility for the accuracy, completeness and timeliness of the data. This includes consistency between data recorded in the case report form (CRF) (study records) and the source documents (medical records). They must be able to explain any discrepancies. Alteration to the CRF should be initialled and dated and should not obscure the original entry. All computer records should be made using programs employing audit trails. Safe storage of the trial records and documentation (including electronically stored data) is necessary during, and after closure of, the trial for the requisite time period (dependent on trial type). This can be up to 25 years for maternity records. The CI is responsible for ongoing mandatory reports during the course and at the end of the trial. This includes progress reports, annually to the medicines and healthcare products regulatory agency (MHRA), funding bodies, etc.; safety reporting of serious unexpected adverse events (SUAES) and suspected unexpected serious adverse events/reactions (SUSARs) (see below); premature suspension of the trial, for example safety reasons; and final reports to the MHRA, M/LREC, sponsor and funding bodies.

When Are Studies Not Covered By The European Union Directive?

When a medicinal product is used in the manner within the terms of its marketing authorisation, or patient allocation is not dictated by protocol but falls within the remit of current practice, the regulations governed by the EU Directive are not required. This also includes when the decision to prescribe the IMP is independent from the decision to include the patient in the trial. This includes mechanistic trials which are not part of clinical research into the efficacy and/or safety of an IMP. Psychotherapy and surgery trials with no IMP comparator, and diet trials with no IMP, are also not covered by these laws. This regulation is also not relevant when a patient undergoes diagnostic or monitoring procedures that are part of normal clinical practice, or when data are analysed using epidemiological methods.

The Medicines And Healthcare Products Regulatory Agency

The MHRA is the government agency responsible for ensuring the safety of medicines and medical devices in the UK. It considers no product to be ‘risk-free’ but applies robust and fact-based judgements to ensure that benefits to patients and the general public justify the risks. The MHRA monitors medicines and devices and ensures, when necessary, that prompt action is taken to protect the public. Within the remit of the MHRA greater access to products and the timely innovation of treatments benefits patients and the public.

The MHRA has produced an algorithm to enable researchers to clarify whether their research question falls within the scope of the EU Clinical Trials Directive. The MHRA will also advise on an individual basis ( www.mhra.gov.uk ).

All trials falling into the remit of the EU Directive legally require Clinical Trials Authorisation (CTA) from the MHRA ( Fig. 15.2 ). If the trial is international, similar approval will be required from any competent authority in each member state. The MHRA must make a decision within 60 days of application. An Investigator Brochure must be kept for all clinical trials, which is a compilation of all the relevant clinical and non-clinical data available regarding the investigational product in human subjects.

EudraCT

This has now been superseded by the latest Regulation and the CTIS register.

International Standard Randomised Controlled Trial Number

In June 2005, the International Committee of Medical Journal Editors ( ) issued a statement that, after 1 July 2005, all trials must be registered prior to recruiting the first subject as a prerequisite to publication, thus ensuring a comprehensive, publicly available database of clinical trials. Randomised controlled trials and other studies designed to assess the efficacy of healthcare interventions should all be registered. The International Standard Randomised Controlled Trial Number (ISRCTN) Register is owned by the ISRCTN, a ‘not for profit’ organisation, and the scheme is administered on their behalf by Current Controlled Trials Ltd.

Application for an ISRCTN is the responsibility of the sponsor or CI and is undertaken online at: www.isrctn.com . The form is divided into five sections:

• 1.

  Applicant details – the contact details of the person making the application. This should be the person who will deal with any queries regarding the application.

• 2.

  Sponsor details – the organisation taking primary responsibility for ensuring the study design meets the standards of GCP and that measures are in place to ensure appropriate conduct and reporting.

• 3.

  Chief investigator (lead principal investigator) – contact details for the individual with legal and scientific responsibility for the trial (also required for multicentre trials) ( Fig. 15.3 ).

  

• 4.

  Details of the trial – from the protocol.

• 5.

  Additional information – general information about where you found out about the ISRCTN scheme.

Receipt of the online application will be acknowledged by e-mail, and after the administrators have checked the eligibility of the application, an administrative charge will be made. The 2021 rate is currently GB£226 + tax per entry. This may be reduced or waived for trials in developing countries. There is also a reduced rate for organisations registering more than 100 trials. Once payment is received, the ISRCTN Editorial Office informs the applicant and the CI of the ISRCTN assigned to the trial, and the record will appear in the register. This number should then be used on trial documentation.

meta Register of Controlled Trials

The metaRegister of Controlled Trials ( m RCT) was initiated in the UK in July 1998 as a result of an initiative involving the UK Medical Research Council, the National Health Service Executive, medical charities, pharmaceutical companies, the UK Cochrane Centre and journal representatives (i.e. BMJ and Lancet ). This is an international searchable database of current ongoing randomised controlled trials in all areas of healthcare. All trial entries are currently in English, although there is an introduction in French, German, Spanish and Italian, with other languages to be added at a later date.

The m RCT has been formed by combining registers held by trial sponsors from the public, charitable and commercial sectors. It is a free service which aims to:

• Facilitate those wanting to be confident they are aware of all trial evidence available relevant to a particular question (clinicians and scientists)

• Assist research funding bodies who want to make funding decisions in the light of information about ongoing relevant research, thus avoiding duplication and facilitating collaboration

• Inform potential participants regarding ongoing trials they may wish to consider.

Although not compulsory, it would be prudent to register any clinical investigation involving an intervention into all three registers.