A clinical trial is usually performed using some kind of comparator. This could be another drug on the market, or a customized formulation with the same characteristics as the drug formulation to be tested in the clinical trial — a placebo. Here I delve into developing your placebo and how to overcome common obstacles.
Developing your placebo — Starting with the simplest route
The development of your placebo can be as challenging and cumbersome as the development of your new drug product. It depends a lot on the design of your clinical trial but also on the characteristics of your drug product.
When developing a placebo, the easiest way would be to just remove your active drug substance, keep the formulation as is, and you’ll have a well-working, good-enough placebo with all the necessary features. This might work if the drug substance wouldn’t impact things such as taste, appearance, viscosity, or smell. I would call this the simplest placebo to develop. It can be used for multiple routes of administration if all necessary features and characteristics stay the same.
But this is not always possible, and there are cases with more complexity involved.
Examples of trickier cases
Let’s say your drug product is an oral formulation with a specific taste, color, or smell. You end up developing a placebo formulation where you must add something extra to compensate for the characteristics the drug substance brings to the active drug formulation. This can be done, for instance, by using bitter-tasting excipients if the active drug formulation has a bitter taste, or by adding an inert coloring agent to make the placebo formulation and the active drug formulation look the same. This makes the development a bit more complex but with a thorough understanding of what kind of excipients can be used, it will not be too hard to do.
If you have an active drug formulation to be administered parenterally that features a specific color, there might be trouble. Parenteral drug products on the market aren’t allowed to contain coloring agents and hence there are no approved coloring agents by the regulatory authorities for parenteral administration. If this is the case, you may use vitamins to color your placebo formulation. They usually hold a strong color, but you need to be aware that vitamins are not inert. They have a biological activity and the effect of adding this kind of coloring should be taken into consideration not to affect the outcome of your clinical trial.
Another common feature for active drug formulations is suspended particles of the active drug product. If they appear in an oral liquid formulation, this can be quite easily solved by adding an inert non-dissolving excipient. However, if they are present in a parenteral formulation, this is very difficult to overcome. You want to avoid non-dissolving particles in a parenteral formulation, which, depending on the route of administration (i.e., subcutaneous or intravenous), will stay under your skin or enter your bloodstream. In such a case, you might look at the clinical trial study design instead and have an unblinded nurse administering the drug to the patients, or use a normal saline solution as placebo and cover the syringe with aluminum foil, for example, to mask visual differences.
Final takeaways
As you can see, there are many ways to handle the development of your placebo, if needed, but it all comes down to the characteristics of the active drug formulation and which of those you need to mask. Just seek advice from an expert in formulation development with experience from different clinical trials, and they will come up with a solution to your placebo development obstacles.
Interested in learning more? Watch our webinar “The Road to First-in-Human Trials: Insights from a Real-World Example”:
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