Clinical trials

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. The general rule is that valid informed consent must be in place for participation. This may be 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 to clinicians who have formulated a 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 medical and health-related 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 (SLV). SLV has a specialist agency for Clinical Trials (Klut). https://legemidelverket.no/godkjenning/klinisk-utproving 

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 (see phase 4 below). This is important because the use of the product will encompass a broader segment of the population than those who participated in the trials that formed 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 strictly regulated and systematically planned. Development takes place in phases. 

Phase 1 is human pharmacology ‒ basic factors such as toxicity and how the body metabolises the medicine in 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 (See also: Payment of research subjects). Some phase 1 studies may entail an unknown risk, others are more likely to entail discomfort than risk. Such studies often include 100 people. 

Phase 2 provides an impression of whether the drug has the desired effect, as well as what dosage and duration of treatment are required. The studies are often short, with surrogate endpoints. Typically, around 1,000 patients participate, and the new drug is often compared with a placebo.  
 
Phase 3 studies, so-called studies to determine therapeutic effect, often include 3,000 patients. The studies aim to confirm the drug’s efficacy and adverse effect profile in the relevant patient group (efficacy and safety). The study usually has “hard” endpoints such as death or morbidity. In phase 3 studies, the drug studied is most often compared with the best available treatment. Phase 3 studies are a crucial part of the foundation for applying for marketing authorisation. 
 
Phase 4 studies go under many names, including: “postmarketing studies”, “real-life studies” or “therapeutic use”, and are intended to observe safety under conditions of normal use in the population Phase 4, which will often include 1,000 patients, also may consider potential health-economic aspects. 
 
The pharmaceutical industry often uses multicentre studies to enable rapid inclusion of patients with a view to achieving 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 principal investigators who may have little involvement in the project as a whole, for example in analysing data, which is otherwise a common task for principal investigators on individual projects.

Challenges of commissioned research

As previously mentioned, clinical trials usually take the form of commissioned research. In 2021, SLV received 144 applications for clinical trials, 60 per cent of which were classified as commercial. 
 
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 principal investigator completes their 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 company 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, i.e., ongoing verification that all aspects of the study are conducted as planned, is an important aspect of GCP (Good Clinical Practice). 
 
Commissioned research is a business contract between the principal investigator or employer and the pharmaceutical company (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. 

Challenges in researcher-initiated clinical trials

The complexity of clinical trials has increased over the years. Health personnel who wish to carry out clinical trials cannot be expected to be experts in all the relevant regulations and procedures. The university clinics have therefore created units that provide the individual clinical researcher with help in organising and carrying out clinical research projects, including clinical trials. 
 
The Norwegian Clinical Research Infrastructure Network – NorCRIN (www.norcrin.no) is a network of such research departments. NorCRIN has drawn up national procedures (Standard Operating Procedures - SOPs) for clinical trials of medicinal products. NorCRIN is part of the European Clinical Research Infrastructure Network – ECRIN (ecrin.org). 

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 pharmaceutical regulatory authorities’ requirement 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 «EMA 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. 

Globalisation

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 low-income 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 difficult to follow up patients and provide access to effective treatment once the trial has concluded. 
 
(See also the research ethics guide Medical and health research in low- and middle-income countries.) 

Publication

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 that 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.

This article has been translated from Norwegian by Jane Thompson, Akasie språktjenester AS. The 2022 updates were translated by Samtext AS.

Literature

Bell RF, Wisloff T, Eccleston C, Kalso E. Controlled clinical trials in cancer pain. How controlled should they be? A qualitative systematic review.  Br.J. Cancer 2006;94:1559-67

Declaration of Helsinki: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

Lov om medisinsk og helsefaglig forskning (Helseforskningsloven, Health Research Act): https://lovdata.no/dokument/NL/lov/2008-06-20-44 

Lov om medisinsk og helsefaglig forskning (Helseforskningsloven) med veiledning og merknader [with guidance and notes]: www.helsedirektoratet.no/tema/helseforskningsloven