Clinical trials

A clinical trial involves the testing of a new medicine (or other therapy) to evaluate whether it is effective and safe. Clinical trials of drugs can be divided into those assessing the treatment of a disease (e.g. asthma) or those assessing treatments to prevent the occurrence of significant healthcare events in the future (e.g. stroke). Clinical trials provide the quantitative information about the benefits, adverse effects and possible uses of new drugs that allows prescribers and patients to make rational decisions in relation to drug therapy. The information will provide the relative risk reduction (RRR), absolute risk reduction (ARR), the numbers needed to treat (NNT) for one to be better off on treatment than comparator.

Preclinical research

Preclinical research answers basic questions about a drug’s safety, and require substantial in vitro and in vivo laboratory investigations, performed under good laboratory practice (GLP: FDA GLP guidance can be found in their Electronic Code of Federal Regulations), which ultimately provide detailed information on dosing and toxicity levels.

Drug Development and Regulation

This is a narrated slide-set comprehensively covering drug development and regulation, presented at a level for first year medical students. Authored by Prof. Simon Maxwell, University of Edinburgh (s.maxwell@ed.ac.uk).

Approval to begin a clinical trial

Each national agency will have its own procedures and terminology, but will essentially require some process of approval for each trial protocol. In the United States the FDA require submission of an investigational new drug (IND) application for approval by a specialist review team, before any clinical trial is allowed to begin.

Human subject protection

Adherence to the principles of good clinical practices (GCPs), including adequate human subject protection (HSP) is universally recognised as a critical requirement to the conduct of research involving human subjects. An essential component of HSP is ensuring informed consent is sought from every trial participant. Many countries have enshrined GCP principles as laws and/or regulations.

Clinical research (the drug trial process)

Clinical trials that form part of the drug development process are conducted in progressive phases which are designed to assess a new medicine for safety and effectiveness. Each phase must be successfully completed before the next can begin.

Phase 0 trials are small (10-15 subjects) first-in-human trials. Typically a suboptimal drug dose is tested to generate preliminary data on a drug’s pharmacodynamics and pharmacokinetics.

Phase 1 trials are slightly larger studies (20-100 subjects) spanning several months, with the aim of evaluating the safety and tolerability of the new drug, and determine dosage ranges. These studies can also begin to identify early side effects. Some phase 1 trials are carried out in healthy subjects, others in patients with specific health conditions who are willing to try an experimental treatment. Around 70% of phase 1 trials progress to phase 2.

Phase 2 trials (several hundred subjects) spanning several months to two years, are designed to evaluate the efficacy of a drug in the target patient group. This level of trial is usually randomised, double-blinded and placebo controlled and would be expected to identify further side effects. Approximately 33% of phase 2 trials progress to phase 3.

Phase 3 trials (300-3000 subjects) taking 1-4 years, are designed to confirm the effectiveness of a drug observed in a phase 2 trial. Larger subject numbers increases the statistical veracity of the results. Phase 3 trials will often compare the new drug to existing therapies (active comparators), and will potentially identify rarer side effects. Although effectiveness of a trial drug is best assessed in a large trial, in the case of rare diseases, by definition the available patient cohort limits the size of the trial.

Phase 4 of the clinical trials take place after a drug has been marketed and typically involve post-marketing safety monitoring following use in the general population. This level of investigation provides additional information in respect of the treatment’s risks and benefits, informs its optimal use, and can identify any side effects resulting from long-term use.

Clinical Trials

This is a 30 minute narrated slide-set comprehensively describing the clinical trial process, including discussion of crucial requirements for good trial design, execution, and analysis. The presentation is at a level for first year medical students. Authored by Prof. Simon Maxwell, University of Edinburgh (s.maxwell@ed.ac.uk).

Regulation of clinical trials

Clinical trials are strictly regulated, to ensure they are run ethically (with the full consent of everyone taking part) and that they are safe. These conditions are achieved by having the trial protocol reviewed scientifically, in a process of independent scientific (peer) review to assess the potential risk/benefit ratio of the proposed therapy, and review by an independent ethics committee. Each centre taking part in a clinical trial must be assessed to ensure it has the staff, equipment and expertise to carry out the trial according to the precise study plan detailed in the trial’s protocol. Every trial has a ‘sponsor’ who is responsible for the conduct of the trial, this may or may not be the organisation funding the trial. Funding bodies can include government organisations, charities, universities, pharmaceutical, biotechnology or medical device companies. Management of trials, monitoring and required lab work is often outsourced to contract research organisations (CROs).

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH.org) issues standardised guidance describing a level of Good Clinical Practice that is adhered to by trial sponsors from many countries including the United States, the European Union, Japan, Canada and Australia.

ICH Guidelines

This webpage provides access to all of the guidelines recommended to achieve greater international harmonisation of technical requirements which aim to ensure that safe, effective, and high quality medicines are developed and registered in the most efficient and cost-effective manner. The main goals of the harmonisation process are to prevent unnecessary duplication of clinical trials in humans, and minimize the use of animal testing without compromising safety and effectiveness.

Clinical Trials

Online clinical trial registries

Centerwatch.com , clinicaltrials.gov and the ISRCTN registry are a few of the online resources providing access to registries of approved clinical trials. These resources include details of proposed, ongoing, completed or terminated trials and may provide access to trial results data. They are essential in ensuring that any trial that has been started is listed, even if it is never completed or published.