| Drugs don’t come easy

Taking a critical look at clinical trials

Today, many fatal or permanently debilitating diseases have better survival rates than in the past, as a result of the development of medical studies, and consequently, vastly improved treatments. However, because of the risks associated with testing new therapeutics, ethical considerations are paramount, and procedures to implement ethical practices are often very rigorous.

Ethics in clinical trials have become more stringent over the years. According to Dr. Teresa Trippenbach, a professor and bioethicist on the Clinical Studies Ethics Board at The Montreal General Hospital, this is a fairly recent change. One of the earliest studies that Trippenbach took part in was in the early seventies; it was a relatively low-risk and that involved administering caffeine to premature babies in order to treat them for apnea. “Back then, we didn’t need written informed consent from the parents for such small procedures,” says Trippenbach. “It was only in the eighties that written consent became required for even the smallest procedures.”

Today, before any clinical trials can be carried out, the procedure must be approved by an ethics board such as the one Trippenbach is on. One of the major considerations is preventing any participant from feeling coerced into taking part in the study. For instance, because there is a widely-held held belief that “the physician is right,” getting doctors to ask participants to take part in a clinical trial is not ideal. Consent forms are thoroughly reviewed to make sure participants receive full disclosure, and to clarify that participation is completely voluntary. The principal investigator’s role in these studies is to determine at which point the patients should receive the intervention, design the trials, and create a protocol to send to the ethics board. “It wasn’t until the late eighties or nineties when investigators became legally responsible. When we take something on as an investigator, we need to know that we are responsible,” states Dr. Amit Bar-Or, a neurologist and neuroimmunologist at the Montreal Neurological Institute.

In order to study the effectiveness of a drug in a clinical population, there must be two groups, with only one group being given the novel drug. The other, a control group, is either given a placebo (a substance without an active ingredient used as a control in an experiment), or another drug that is currently considered a standard treatment. Patients are not told which group they are in. Before the onset of the trial, patients are explicitly told about their chances of receiving the drug or a placebo. Though it does mean that one group may not be receiving treatment that could potentially help their disease, this set-up is required in order to determine how effective a drug truly is.

Clinical trials are carried out in a series of phases. Prior to human clinical trials, efficacy and toxicity of the experimental drug, among others variables, are recorded from in-vitro or laboratory animal studies. If the drug succesfully passes these stages, it officially enters phase one, wherein studies are done on healthy individuals in order to determine whether or not it is safe, so clinicians can proceed to further trial stages. Phase one studies are often considered to be the most controversial, as healthy individuals are offered monetary compensation to participate in testing the safety of a drug. Once a drug enters phases two and three, it is tested in patient populations for safety and efficacy. Even though, at this stage, the safety of the drug has still not been fully determined, these patients can potentially receive physiological benefits from the drug, unlike the stage one testers. If a drug successfully passes through phase three, it is allowed into the market for a wider population, during which the drug continues to be monitored for long-term effects. Often it is not until reaching the wider population level that certain negative effects are revealed. Regulatory agencies expect animal model testing to be a necessary step, but there has been a recent shift to consider the fact that for certain clinical trials, the animal model step may be skipped.

“The reality is, there will be risks associated with any clinical trial,” Bar-Or admits. “If we knew [the new drug] was better, in terms of safety and efficacy, we wouldn’t need to do the clinical trial.” An important concept in clinical trials is that of equipoise. Equipoise determines whether particular activity – like the administration of the drug – strikes the right balance between potential benefit and risk. In the case of clinical trials, this means looking at whether the effectiveness of the drug outweighs the risks of carrying out the trials.

Unfortunately, only a small proportion of the drugs that enter clinical trials succeed to proceed through all the phases. According to Joseph Tota, a PhD candidate currently involved in the Carregeenan-gel Against Transmission of Cervical HPV (CATCH) study at McGill, the biggest obstacle faced in this type of research is getting the green light on the study. “Most of the major obstacles come at the beginning [when] you design a trial and you hope there is merit to it. Our study was eventually ranked first in the application pool after multiple rounds of applications…[We also needed to make sure we met all the] ethics requirements – Health Canada requires very stringent requirements before going through testing,” he said.

Many clinical trials are funded by pharmaceutical companies, though a proportion are also funded by government agencies. Money from the funding agencies goes straight to the institutions that carry out the research (i.e, McGill), which prevents the conflict of interests that could occur if the money was given directly to clinicians. Conflicts of interest could occur if doctors were given a certain amount of money per subject recruited into the study.
It is clear that there are many important considerations underlying clinical trials. Because of the nature of the studies – looking at patient populations and testing novel therapeutics – there are many potential risks in carrying them out. And though many drugs don’t pass through all the clinical trial stages, we hope that the ones that pass introduce a large benefit to society.