III clinical trials
These often involve many thousands of patients designed to quantify the extent to which the drug is effective and in what patient groups. Given the increase in numbers of patients exposed less common side effects may be seen and the benefit/risk ratio can be more clearly estimated. These are the key regulatory studies, and as such inform the labelling and patient information for the drug when it is marketed. At the same time as these trials are underway, the pharmaceutical company will be investing considerable efforts into scaling up the manufacturing process, and completing the stability studies on the dose form and packaging which will be taken to market. While various formulations can be tested in Phase II, Phase III studies must be conducted using the final formulation. A key challenge with biotechnology products, which are not manufactured using conventional chemistry, is to develop manufacturing processes and robust assay methods which can guarantee consistent levels of biological activity between batches.
During Phase III, the regulatory affairs department within companies will be pulling together the large amount of manufacturing, preclinical and clinical data necessary for making a formal application to the relevant regional and national regulatory authorities for a product licence. Each major regulator requires the data structured in a different way, therefore first priority will usually be given to submissions to the FDA and the EMA. Review times by these regulators vary based on circumstances, but it usually takes approximately 1 year.
Based on the data submitted, each regulatory authority will produce a factual summary of the preclinical and clinical results, including the key safety information and dosing instructions. This document will also state whether the marketing approval is general or restricted, e.g. hospital use only. The relevant document issued by the EMA is called the summary of product characteristics (SPC) and provides the key information required to aid a decision by the prescriber as to whether the drug is indicated. A second valuable document is the European Public Assessment Report (EPAR), found on the EMA website, which provides a more detailed summary of the Agency's review of the data submitted. Over time, the SPC will be updated by the company as key new information becomes available, but clinical publications and treatment guidelines are also invaluable in providing additional detail which will not be found in the SPC.
In the UK, each new drug in the British National Formulary has an inverted triangle symbol next to it reminding doctors that it is a new product and that any suspected adverse effects should be reported to the Commission on Human Medicines (CHM) via the yellow card scheme.
Factors to consider in Phase III trial design
The main objective of a Phase III trial is to establish the effect of a new drug while controlling for bias and confounding. This is achieved by randomly allocating trial participants to treatment groups, ensuring blinding is performed where possible, having a representative control group and analysing results on an intention to treat basis. Stratified randomisation is a technique that can be used to balance groups with respect to confounding variables such as age, although it is important to avoid over‐stratification as the trial must include an adequate number of patients for each arm and stratum. Blinding study participants, investigators and/or assessors to allocated drugs helps to reduce bias, although this must be balanced with practicality and cost. For example, in a trial of thrombolytic therapy for acute ischaemic stroke, the drug alteplase is being compared with another drug tenecteplase. Alteplase is administered as an intravenous bolus followed by a 1 hour infusion, whereas tenecteplase is administered only as a bolus, which makes blinding of investigators and participants challenging. The options in this setting are to accept the limitation of only blinding final assessors of the trial data or employing a ‘double‐dummy’ approach that utilises a placebo for each intervention, although the latter approach is often less practical and more expensive.
It is important to carefully select the study population and endpoints to ensure that the population is representative of the target patient group who may benefit from the drug and that the endpoints are of sufficient clinical relevance to justify drug licencing if proven to be effective. The primary endpoint should therefore be clinically relevant, measurable and potentially sensitive to the effects of the new drug. The trial should aim to have a high proportion of subjects with complete data and the results should generally be interpreted on the basis of intention‐to‐treat (all patients who entered the study) rather than per‐protocol (only the patients who completed the protocol). A large dropout rate may indicate a drug that is unlikely to be commercially successful. Additionally, it is also important to ensure that the sample size is large enough for the trial to be sufficiently powered to detect a meaningful difference between the drugs if one exists and avoid a type II error where an effective drug is incorrectly rejected due to the trial being underpowered.
Newer approaches to Phase III clinical trial design
The above description of a clinical trial is based on a very traditional model that is generally straightforward and well‐understood by the research community but is often inflexible, time‐consuming and expensive. With this in mind, new adaptative approaches to clinical trial design have been developed that aim to be more flexible, efficient and potentially more informative. These aim for continual learning and adaptation as the data accumulate, which can result in changes to the allocation ratio, sample size, eligibility criteria and treatment arms. This has the potential to reduce the resources and time required for trial completion, reduce the number of patients exposed to inferior treatments and improve the likelihood of trial success. For example, if an interim analysis suggests a particular subgroup has a more favourable response, then the trial can be modified to solely or predominantly enrol patients from this subgroup. However, decision rules must be prespecified before the trial is commenced and are generally based around an iterative simulation process of ‘best’ and ‘worse’ case scenarios. While such adaptive trial designs can be more effective in terms of resources and time, they can be less readily accepted by regulatory agencies. They can also be limited by the potential to prematurely stop a trial for futility when the new drug is performing less well than the comparator initially but having an effect that might manifest itself later. The extent to which adaptive designs will be utilised in clinical trials remains to be fully established.
The new drug compound for neuroprotection has now been tested in Phase III clinical trials and has shown good efficacy with an acceptable side‐effect profile. It gets approved by the regulatory authorities and the company wants to start marketing the drug. Is there a limit to what the company can do in its marketing strategy? How is its safety monitored? What happens if concerns about side effects become apparent?
Phase IIIb and IV studies
Phase III trials will generally have included selected groups of patients based on strict inclusion and exclusion criteria that will form the basis of its licenced indications and the product can only be marketed on this basis. For this reason, further studies will often be performed to either widen the licence indications to broader groups of patients such as the elderly (Phase IIIb) or evaluate drug safety and efficacy in a real‐world setting, over the longer term or against comparators, often involving many thousands of patients (Phase IV). It is important to emphasise that even though a drug may obtain a licence, it does not necessarily mean that there will be widespread use in patients, as many countries also mandate a health economic evaluation to ascertain its cost‐effectiveness (see Chapter 3).
Pharmacovigilance
There is now a greatly increased obligation on pharmaceutical companies to set up risk‐management
