What about the smell? - Challenges of clinical trial design and maintaining blinding

What about the smell? - Challenges of clinical trial design and maintaining blinding

When designing a clinical trial, one of the biggest factors that needs to be thought about is blinding. In clinical trials, there is a risk of expectation influencing findings so if a patient knows which treatment group they have been allocated, there is a risk that this could bias results. In controlled trials, the term “blinding” refers to keeping study participants, those involved with their management, and those collecting and analysing clinical data unaware of their assigned treatment so that they cannot be influenced by that knowledge. If patients are not blinded, awareness of group assignment may affect their behavior in the trial, and their responses to subjective outcome measures.

Blinding may not always be easy or possible, and it goes much further than just keeping the name of the treatment hidden. Differences in appearance of the drug used in the study could give a clue to its appearance. Differences in taste, smell, mode of delivery, or even colour may also affect perceived efficacy, so these aspects should be identical in each treatment group. PHASTAR Senior Statistician, Stephen Corson, recently published a paper with the results from a study aiming to investigate whether adding levomenthol to an ibuprofen gel could reduce the time taken for an analgesic effect to occur in patients with soft-tissue injuries.[1] Menthol produces the sensation of cooling without reducing skin temperature and following topical application, menthol has an anaesthetic effect. Menthol can also enhance the skin penetration of topical analgesics, potentially increasing their effectiveness in relieving pain. But how do you blind menthol? That was the challenge that Stephen faced when designing the study procedures for this trial. Here he explains how these issues were addressed.

For statisticians, clinical trials allow us to apply our knowledge to real world problems intended to improve the health and well-being of the population. Every day presents us with new challenges or interesting things to consider and so we always have plenty to do. What may surprise you is that our challenges are not always related to the numbers.

In a recent study looking at pain relief gels, the study team were interested in assessing whether the addition of menthol to the standard product would reduce the time taken for users with soft tissue injuries to achieve pain relief. The logic behind this idea was as follows: when you apply a pain relief gel to your skin you feel a tingling sensation as it is absorbed which gives you a sensation of pain relief. This gradually fades and so you will generally feel an increase in pain until the active ingredient, usually ibuprofen, kicks in. Menthol reportedly acts as a ‘cooling-mimetic’ agent which produces the sensation of cooling when applied to the skin. The manufacturer was keenly interested in knowing whether a gel containing menthol would increase the duration of skin cooling so that you get a longer sensation of pain relief while the active ingredient gets to work. With that in mind, we set off to design a study where we have two groups of patients: one testing a gel with menthol and one testing a gel without menthol.

While the idea may seem simple, there is one important issue to contend with! Menthol is an alcohol from mint and so it has a rather distinctive smell. And here-in lies the problem. To ensure reliable test results, we don’t want the patients knowing which gel they are testing (known as single blinding). How do you ensure that the patients using the medicine in the trial don’t know what medicine they are taking when one has a very distinctive smell? Cue some very confused statisticians and medical professionals alike.

Well the solution that we came up with is a little bit unorthodox. In terms of the products themselves, you cannot make them smell the same otherwise there will be no comparison. Therefore, the only way to stop people from associating menthol with the medication is to put them in a menthol rich environment. Lightbulb moment! If we put people in a room, like a steam room, where the ventilation system is pumping menthol into the air, then you won’t be able to tell if the smell is coming from the medication or not. And that is what we did.

As a result, patients had to sit in a custom room for 2 hours during the test where the air being circulated was combined with menthol.

As this example goes to show, life a statistician is a lot more than just number crunching. Statisticians get involved in all stages of clinical trials, all the way from trial design to final analysis and we have lots of interesting and challenging questions that need to be answered along the way!

  • [1] Wade AG, Crawford GM, Young D, Corson S, and Brown C. Comparison of diclofenac gel, ibuprofen gel, and ibuprofen gel with levomenthol for the topical treatment of pain associated with musculoskeletal injuries. Journal of International Medical Research 47(9); 4454-4468. DOI: 10.1177/0300060519859146