Group1: Clinical trials

Clinical trials – Phases

The development of a new therapeutic agent is a long process, which starts in the lab with scientist screening for potential drugs in vitro and performing animal testing. This step is generally referred to as preclinical testing and does not involve  human subjects.

Once a drug has been selected for clinical trial, a four step procedure is being executed, which has the aim of delivering a safe drug to the market. The four stages should provide answers to different questions and each step relies on a positive result of the previous one. In the following the different stages will be described briefly. It is also noteworthy, that this general procedure might be different in special cases, where it is not applicable (e.g. treatment via surgery) or that phases might overlap [1] (following section).

Phase I – Is it toxic?

Only very few generally healthy volunteers are involved. Sometimes, patients who have exhausted the pool of standard treatments are admitted to this phase. In this phase the immediate safety of the agent is assessed (e.g whether a drug is toxic or an implant is safe and delivers the correct dosage). Furthermore, the maximally tolerated dose is determined by gradually increasing the dosage in a small number of volunteers. Once the a determined level of toxicity is observed it (or a previous one) is set to the maximally tolerated dose.

Phase II – Does it have an effect?

In the next phase, the drug is further assessed in a group of carefully selected individuals. The main goal of this stage is to assess, whether the drug has any effect (biological activity) and is worth further development. The control schemes can vary, be it a case-control study or pre- versus post-treatment status. Since the necessary dose is not yet known, often different doses will be administered. The still very small number of patients does not allow any conclusions on the large scale effect of a drug, but if it is promising it will be accepted for phase III clinical trial. This depends on various factors, like the beneficial and harmful effects of the drug, which need to be evaluated in context of the disease which ought to be treated, but also other factors, such as the size of the target group and general feasibility will be accounted for.

Phase III

Once the non-toxicity and potential use of the compound has been declared, the drug enters phase III of a clinical trial. Now, the drug is administered to a larger group of patients and a proper control scheme is set up. The effectiveness of the drug in comparison to the standard treatment is assessed, which generates clinically relevant knowledge on the new medication. It is difficult to asses harmfulness of a drug in this still relatively short trial periods especially for treaements destined to chronically ill patients, where the duration of medication is potentially indefinite. Also late negative effects can obviously not be controlled for.

Phase IV – Follow up

As mentioned above, the problem with most clincial trials, that survived phase III are potentially late effects and effects of prolonged administration of the drug. Therefore follow-up studies are being held, which aim to identify those. These studies are either referred to as follow-up of phase IV trials. The justification of those studies are prominent examples of drugs having a positive effect in the first place, but which affect the organism in a harmful way at a later state (e.g. cyclooxygenase 2 (COX2) inhibitors for arthritis treatment, that turned out to increase the risk of cardiovascular problems) or a device that might fail after a few years.

Drug developement workflow

The diagram depicts an overview of the drug development process from the first lab testing, over the clinical trails to the follow-up studies [2].

The cost of clinical trials

In a recent study, the cost of clinical trials has been investigated using data from 7 large pharmaceutical companies. As can be seen in the plots, the amount spent depends on the stage of the trial, with phase II being by far the most expensive one. The largest proportion of the overall amount spent is the cost for personnel.  Most of the variance in the cost of clinical trials depends on protocol design, number of subjects, sites and visits. The number of cooperating countries, especially emerging markets tended to increase the phase III trial duration and thus, with trial duration being another major factor in trial cost, the overall amount of money spent [3].

Cost of clinical trials 2017

Figure 2: Distribution of the costs of clinical trials by phases. The median is depicted as a blue square, the mean as a yellow bar [3].

Cost of clinical trials 2017

Figure 3: The categories which make the largest part of the costs of clinical trials. Costs for personel take the largest part of the budget [3].

A well designed clinical trial can give valuable clinical insight to the effectiveness of a treatment and has therefore the potential to increase patient well being and public health as it provides a sounder rationale for the intervention. The consequences of a not properly conducted or left out clinical trial might be severe. There are several cases of belated clinical trials, that revealed an assumed helpful drug to be harmful. It might be helpful to determine the level of superiority of a new treatment in comparison to the standard procedure, also considering financial aspects [1].