Numerous aspects unrelated to the active agent, such as patient care, formulation and disease variability can influence both objective and subjective measurements. The widely recognized phenomena known as the “placebo effect,” “the Hawthorne effect” and “regression toward the mean” are some of the confounders that can often lead to misleading or unexpected results.
The Placebo Effect
In clinical studies, placebos are used as the basis of comparison in determining the efficacy and safety of a pharmacological therapy. If a drug benefits the patient beyond a pre-defined threshold vs. placebo, it may be said to be efficacious.
Ideally, only the active drug in a study will show any effect (be it positive or negative) on a patient’s signs and symptoms. In many studies, however, the placebo effect can skew the results with a measurable, observable or felt improvement not attributable to an active treatment. For example, in a study of oral antioxidant therapy for dry eye, subjective parameters evaluated with McMonnies’ dry eye questionnaire were significantly improved. But, only antioxidant-treated patients showed significant improvement in tear-thinning time, goblet cell density and metaplasia.1
The placebo effect also manifests in non-psychological parameters. For example, ophthalmic solutions used as placebos in allergic conjunctivitis trials can alleviate symptoms through allergen washout. The pathophysiology of allergy requires contact time with the conjunctiva, so an artificial tear (placebo) instilled in the eye can interrupt this process by washing away the allergen, leading to positive placebo response rates of as high as 70%.2 Tear substitutes used as a placebo in dry eye trials have also shown statistically significant improvement in tear film stability as measured by the Ocular Protection Index (OPI) when compared to baseline measurements.
The Hawthorne Effect
Knowledge that one is being observed or studied can lead to changes in behavior due to what is known as the Hawthorne effect. With regard to clinical studies, the Hawthorne effect will usually cause study participants to be more compliant to their treatment regimen or increase their motivation to carry out instructions beyond the degree to which they would in normal circumstances.
Additionally, patients who receive instructions from a health care provider will often assume the clinician is acting out of concern for their wellbeing, which in turn increases the likelihood of positive subjectively determined self-reported results.
Regression Toward the Mean
This concept is based on the realization that patients are most likely to seek treatment or enter a clinical study for a condition when their symptoms are at their worst. This occurs most commonly in diseases with wide fluctuations in severity (e.g., allergy).
When inclusion criteria for a study require a baseline value that is above an individual’s mean value for their condition as a whole, they may still be included in the study either by a chance high reading at a screening visit or through multiple screening attempts. As a result, the reading for their condition could appear to have improved at subsequent visits (when in reality, it’s just decreasing toward their average value), independent of whether or not they are receiving active treatment.
Patient exuberance to participate in a clinical study and meet inclusion criteria can also influence efficacy results through the inflation of self-reported outcomes during screening and baseline evaluations. Likewise, the desire of the investigator to enroll higher numbers of patients could cause them to stretch baseline scores, which may then cause a patient’s condition to appear to have improved as the study progresses.
Bottom line: Clinicians must be cognizant of these effects both when prescribing medications based on clinical data and when assessing patient improvement on medication.
1. Blades KJ, Patel S, Aidoo KE. Oral antioxidant therapy for marginal dry eye. Eur J Clin Nutr. 2001 Jul;55(7):589-97.
2. Leino M, Ennevaara K, Latvala AL, et al. Double-blind group comparative study of 2% nedocromil sodium eye drops with 2% sodium cromoglycate and placebo eye drops in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy. 1992 Oct;22(10):929-32.