Clinical trial phases I-IV

The clinical trials are used to determine whether a drug is safe and effective in the target population with the overall aim of improving patient care. The process is split into four phases.

Phase I is where the drug is first introduced into humans to determine whether the drug is safe and to establish a tolerable dose. The pharmacokinetics (how the drug is absorbed, transported, distributed and excreted by the body) and phamacodynamics  (how the drug affects the body) are studied in small numbers of healthy volunteers (when ethical). The dose of drug is increased in successive cohorts until the appropriate dose can be established. Data to be analysed could include the comparison between test and control groups, comparison between test groups, temporal factors during dosing and any adverse events recorded.

Phase II studies test the activity of the drug against the disease in larger cohort of patients to observe one or several endpoints. Any drug effects are considered in light of existing therapies or the control arm and observed toxicities. Studies can be single arm with a comparator of a prior clinical trial or clinical experience or, randomised to compare against a control (placebo or standard therapy) or another experimental arm (different doses). One method which increases the likelihood of observing a difference begins with all subjects receive the experimental arm then are randomised between continuing in the experimental arm or being assigned to the control arm.

Phase III involves large randomised studies to demonstrate the efficacy of the drug in the disease setting. Study design needs to take into account the existing therapies used in the target population and how representative would the selected participants be to the target population. Primary and secondary endpoints are assessed.

An example of a phase III study is that of Bapineuzumab (Johnson & Johnson and Pfizer), a monoclonal antibody against beta-amyloid and was tested for efficacy in Alzheimer’s Disease (clinical trials details (2012):

General Results: had some biological effect, reducing tau in CSF (Blennow et al., 2012) and accumulation of Ab in the brain (results of the above trial presented at the 16th EFNS Congress, Stockholm, Sweden 2012). First of four Phase III trials, Bapineuzumab failed to meet co-primary endpoints (Alzheimer’s Disease Assessment Scale (ADAS-cog) and; Disability Assessment Scale for Dementia (DAD)) and Pfizer halted development.

Phase IV studies are conducted after the drug has been approved for marketing. If requested for regulatory reasons, studies are continued to collect data on toxicity in much larger populations.





Clinical Trials regulations and management

By using soundly designed clinical trials we can address important clinical questions.

The process for developing a plan starts with the consulting stage where the research idea, roles and sponsor are discussed. In the development stage, the protocol is planned, trial documents are completed and funding is sought. The time scale, resources and tasks will be defined. Contracts and roles and then trial documents are finalised. Approvals and ethical agreements are obtained for the host organisation and the work to be carried out. For trials of investigational medical products (IMP), the trial must follow Regulations of Medicines for Human Use so that they conform to the EU Directive. Once the trial protocol is written a EuraCT number is acquired from the EMEA and an application for authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) is submitted and favourable opinion from the Research Ethics Committee (REC) is acquired.

A sponsor is an individual or organisation which takes responsibility for initiation, management and/or financing the project.

The clinical trial protocol describes the scientific rationale, objectives, study design, methodology, statistical considerations and organisation. The investigator’s brochure details the precise study plan for execution and ensures that the trial is conducted in the exact same way by all centres. If method of data acquisition differs between centres then it could lead to invalid data.

The essential documents required by the trial enable the evaluation of the quality of the trial conduct and the data acquired. These documents demonstrate compliance of the investigator, sponsor and monitors adherence to the Good Clinical Practice (GCP) guidelines – a set of ethical and scientific standards used internationally that ensures the rights, safety and well being of subjects. The GCP guidelines assures conduct is consistent with the principles of the Declaration of Helsinki, for example: the well being of patients prevails over all; anticipated benefits outweigh/justify the risk; patient consent is acquired; medical doctors make medical decisions for patients; adequate information on the investigational medical product (IMP) exists; there is a clear and sound protocol; favourable opinion is sought from research ethics committee (REC); each member of the team is adequately qualified and trained; there is accurate reporting and verification of data; data protection is in place; IMP is handled with Good Manufacture Practice (GMP).

By implementing GCP, the trial master file (TMF) includes all those documents that help the trial management and the independent auditing, close out and archiving of data. These documents individually and collectively permit the evaluation of conduct and the quality of data. The documents include the protocol – the purpose, method and structure of the trial; ethical and regulatory approvals; qualifications of all staff; participant information e.g., recruitment strategy and consent forms; recording of Serious Adverse Events (SAEs) and; the final report. Data monitoring can include on site source documentation (SDV), on site system review and central monitoring by the Data Monitoring Ethics Committee (DMEC) surveillance. The Trial Steering Committee (TSC) supervises the scientific and ethical conduct of the trial and determines further progress based on reports from the trial managers and DMEC. The trial manager maintains the TMF. Annual progress, safety reports and the final report are submitted to the REC and Medicines and Healthcare products Regulatory Agency (MHRA).

The local study co-ordinator will ensure eligible patients are considered for recruitment, provide patients with information, register patients, obtain consent, allocate the patient into the study according to the randomisation protocols, obtain drug packs and follow up assessments. The trail manager will maintain close communication and oversight with the Pharmacy to the design, conduct and troubleshooting of trials. The manufacture, packaging, labelling, distribution, prescription, storage, accountability of randomised medicines are issues that need sustained and close monitoring.