Clinical trials or studies of the effects of drugs on humans
Clinical trials of drugs on humans are an important part of clinical research. Such trials will always entail risks for the research subjects. This is challenging, both when trials need to be combined with treatment, and when the participants include patients with a reduced capacity to consent.
Funding of clinical trials
The pharmaceutical industry is heavily involved as a commissioning agent in clinical trials (commissioned research). The industry may also make payments (unrestricted grants) to clinicians who have formulated the research question independently of the funding agent. Clinical trials can also be conducted in the absence of any relationship to the pharmaceutical industry, for example with funding from independent institutions such as the Research Council of Norway or the health trusts.
Legislation and rules
All research that includes humans must be conducted within the parameters stipulated in the Norwegian Health Research Act. Clinical trials are also governed by separate regulations managed by the Norwegian Medicines Agency. All clinical trials must be pre-authorised by the Norwegian Medicines agency as well as by the Norwegian Regional Committees for Mediacal and Health Research Ethics.
Commissioned or independent research?
Research commissioned by the industry is usually intended to pave the way for a drug to be approved for general use by the pharmaceutical regulatory authorities (marketing authorisation). A further objective might be to study adverse effects after the drug has been registered and is in general use by the public (pharmacovigilance). This is essential because use following registration will include patients with characteristics different from than those which form the basis for the marketing authorisation. A third aspect which is rarely referred to directly is the potential use of clinical trials for marketing purposes.
Structure of clinical trials
Clinical testing of a new medicine is highly regulated and is structured systematically. Development takes place in phases. Phase 1 is human pharmacology ‒ basic factors such as toxicity and how the body takes up, distributes and eliminates the medicine the body. Healthy volunteers often take part in such studies as trial subjects, but patients may also participate. It is common to pay a fee to healthy volunteers for their participation in these types of studies. Some phase 1 studies may entail an unknown risk, others are more likely to entail discomfort than risk.
Phase 2 provides an impression of whether the drug has the desired effect, as well as what dosage and duration of treatment are required. Those taking part are patients, and generally the new drug is compared with placebo.
In phase 3 studies, so-called studies to determine therapeutic effect, between 500 and 5000 patients are included. The studies aim to confirm the drug's efficacy and adverse effect profile in the relevant patient group, and will form the final basis for the application for registration/marketing authorisation. In phase 3 studies, the drug studied can either be compared with the best available treatment or with placebo.
Phase 4 studies are also known as "postmarketing studies" and are often intended to observe safety under conditions of normal use in the population. In phase 4, potential health economic aspects will also be considered.
The pharmaceutical industry often uses multicentre studies to enable rapid inclusion of patients with a view to the shortest possible time to registration. With multicentre studies, the trial is conducted at more than one institution, either in the home country or abroad. Multicentre studies have local investigators who may have little involvement in the project as a whole, for example in analysing data, which is otherwise a normal task for project managers on individual projects.
Challenges of commissioned research
As previously mentioned, clinical trials usually take the form of commissioned research. In order to implement the studies, the companies must establish contact with competent personnel in hospitals or in general practice. It is important for the companies that the project manager completes his/her part of the work on schedule and with a high degree of precision in relation to the research protocol. To check that the studies are properly conducted, it is a requirement that the patients consent to both the pharmaceutical firm and the regulatory authorities having access to confidential data in their patient records. In practice this may mean disclosure of large parts of the records because relevant information is not always gathered in one place. However, monitoring is an important aspect of GCP (Good Clinical Practice).
Commissioned research is a business contract between the principle investigator and the pharmaceutical firm (the sponsor). It is common to calculate a cost per completed patient, and in some cases the fee is only payable if patients have completed the planned study in its entirety. There is some concern that more important, but less lucrative studies may lose out to commissioned research.
Control groups: placebo, best available treatment or other alternatives?
Control groups should be included in clinical trials to increase the certainty that the effect of the drug has been measured, and not other factors such as the natural course of the disease or the patient's or therapist's expectations. The pharmaceutical regulatory authorities, particularly the US Food and Drug Administration (FDA), which exercises considerable global influence, generally wants documentation that the new drug is superior to a placebo. Demonstrating that the new drug is superior to a placebo will require fewer patients than showing that it is better than existing treatment. Supported by the Declaration of Helsinki, clinicians are more concerned with whether new treatment is better than existing treatment. The requirement by the pharmaceutical regulatory authorities for placebo-controlled studies may come into conflict with the requirement of the Declaration of Helsinki for best available treatment, given that the pharmaceutical industry is most comfortable with placebo-controlled studies. In recent years, the choice of control groups has taken prominence as a significant ethical and scientific issue. The European Medicines Agency has published guidelines stating that research design should be modified to offset ethical objections (see EMEA ICH Topic E 10: Choice of control group in clinical trials). Another challenge associated with some clinical trials is that patients are taken off well-regulated treatment before they embark on a new study. There may also be other deviations from general clinical practice in trial protocols.
Clinical trials are a globalised business. The industry seeks out low-cost regions that are able to offer satisfactory quality. Another challenge is that studies are outsourced to developing countries in which the therapy concerned is perhaps not available to the general public for reasons of cost, and this may strongly influence any decision regarding consent to participate. The absence of a developed health service can also make it impossible to follow up patients with access to effective treatment once the trial has concluded.
The pharmaceutical industry can place restrictions on publication of the study. There are examples of the industry failing to publish according to the protocol, but choosing a more favourable outcome than that specified in the protocol. It has also been documented that studies which find no differences between the treatment groups are more seldom published than those that show positive findings. There may be several reasons for this, among them the fact that journals find them less interesting. In order to overcome this problem, international databases have been established, in which all projects must be registered prior to start-up in order to permit publication in the most renowned medical journals. See also publication bias in the article entitled 'Bias'.