|CONTINUING MEDICAL EDUCATION
|Year : 2019 | Volume
| Issue : 4 | Page : 144-146
Lessons from the past: Avoiding placebo generated increased hair counts
D Hugh Rushton1, Dominique JJ Van Neste2
1 School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
2 Brussels Hair Clinic, Brussels and Skinterface, Tournai, Belgium
|Date of Web Publication||19-Aug-2019|
Dr D Hugh Rushton
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rushton D H, Van Neste DJ. Lessons from the past: Avoiding placebo generated increased hair counts. Int J Trichol 2019;11:144-6
| Introduction|| |
During the past 30 years, the evaluation of scalp hair and in particular, methods employed in the Food and Drug Administration (FDA)-approved clinical trials failed to fully appreciate potential confounding issues. In 1985, hair regrowth was reported to show the reversal of male pattern hair loss in subjects receiving topical 2% minoxidil and placebo, as evaluated by visually counting hair in a 1” diameter circle (2.5 cm). Concerns were raised following this publication as to how a placebo could induce hair regrowth in male pattern hair loss. As part of an Upjohn sponsored, double-blind, 2% minoxidil, placebo-controlled study, visual hair counting was compared with the validated quantitative unit area trichogram. In the placebo group, no significant increase in any hair variable was observed with the unit area trichogram analysis, while significant increases were recorded in the same site and same individual, with visual hair counting. This study showed counting experience resulted in increased hair counts where none existed. This study resulted in visual hair counting being abandoned, and the development of photographic imaging techniques ensued.
The vast majority of hair researchers then adopted an FDA approved photographic method in double-blind placebo-controlled hair growth evaluation studies, which relied on “visible hair” count measurements to determine treatment efficacy. However, these investigations also reported increased hair growth in subjects treated with placebo lotions, again raising questions as to how “visible hair” on photographs could be interpreted as improved hair growth in an individual using a placebo lotion?
In 2011, the evidence-based (S3) guidelines (revised 2017) for the treatment of androgenetic alopecia in men and women was published  and acknowledged “that the reported placebo rate in most of the minoxidil studies is very high.” In 2012, a Cochrane review of androgenetic alopecia  was also concerned about placebo generated hair growth. However, both publications failed to address either the nature of this confounding or its implications on the observed drug-associated therapeutic effect.
We evaluated exclusively those studies rated by independent experts as being of the highest quality from the publications in the S3 guidelines and examined the nature of the so-called “placebo effect” in relation to the reported active drug effect limited to a 1-year duration. For each study, we selected the placebo data time point reflecting the longest exposure to placebo, between 24 and 48 weeks (mean 41 weeks ± 9 standard deviation [SD]) and compared this value where possible with the reported baseline hair count.
There were 13 placebo-controlled studies involving a total of 4743 participants. One thousand four hundred and ninety-one participants were included in six studies where topical minoxidil was compared with a placebo lotion, both of which contained propylene glycol. About 74% of participants in this group were female. Three thousand two hundred and fifty-two male participants were included in seven oral finasteride or dutasteride studies, compared with men taking placebo pills.
Active drug dosages matched those in clinical practice, i.e., topical application of 2%, and 5% minoxidil solutions (1 ml twice daily) or oral finasteride (1 mg) or dutasteride (0.5/0.1 mg) daily. The mean treatment duration was similar between oral and topical groups. All studies employed the FDA approved photographic method and hair count changes from baseline are given as hair per cm 2 (absolute) or per cent (relative) changes from baseline [Table 1] and [Figure 1].
|Figure 1: Hair count changes from baseline are displayed as hair per cm2 (absolute) or per cent (relative) changes from baseline in a series of clinical studies. (a) The mean absolute and relative hair count changes from baseline are shown for active (plain black bars) versus placebo groups (empty or hatched bars). Active groups included topical 2%–5% minoxidil + propylene glycol (PG M 2%–5%), 5% minoxidil foam (Foam M 5%), or daily oral finasteride 1 mg or dutasteride 0.5 or 0.1 mg (Oral active). The vehicle in topical placebo groups contained the same concentration propylene glycol (PG placebo empty bars) as the active topical lotions, foam (without PG) in one single study (foam placebo; oblique hatched bars), and oral placebo (vertical hatched bars). Placebo source data appear in table while the mean drug associated changes were taken from the tables published in the S3 report. (b) Displays net mean hair count either as the absolute or relative change. The “net effect” was obtained by deducting the absolute or relative changes reported in placebo groups from those given in active groups for topical lotions (speckled bar, PG M 2%-5% minoxidil), foam (empty bar, Foam M 5% minoxidil), and oral preparations (vertical hatched bar; Oral Active)|
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Absolute changes in hair counts and percentage change versus baseline in the placebo groups are detailed in [Table 1], while drug effects are given in [Figure 1]. Statistical levels of significance (P ≤ 0.05) for mean changes in hair counts were evaluated employing Student's t-test.
| Results|| |
[Table 1] presents the absolute and relative changes (mean ± SD) of “non-vellus” hair counts reported for placebo groups. All studies employing the twice daily, propylene glycol-containing placebo-containing lotion, reported increased hair counts compared to baseline. In contrast, all oral placebo studies reported a decrease in hair counts compared to baseline. The absolute and relative (%) mean hair counts values, between the two groups (topical placebo versus oral placebo) was statistically significant (P<0.0001).
[Figure 1]a presents the absolute and relative (%) hair counts for the active and placebo compounds, while [Figure 1]b presents the net differences, i.e., active minus placebo values.
| Conclusions|| |
From the published placebo-controlled studies employing an FDA approved photographic method, we have highlighted that there is probably technological confounding for the claimed increases in hair counts, raising concerns about the extent of the claimed topical minoxidil efficacy. We suggest that the reported “hair regrowth” associated with topical placebo lotions might be due to propylene glycol influences. A position supported by a mean decrease in the oral placebo group (−3%) and only a negligible increase (+3.4%) in the placebo arm of a topical minoxidil study, that did not contain propylene glycol. Furthermore, the use of non-FDA approved hair evaluation methods, for example,in vivo microscopy  and the unit area trichogram  also found no significant increases in placebo hair counts in subjects treated with propylene glycol-containing lotion.
We note that while the Expert Reviewers of the S3 and Cochrane publications raised concerns about the reported increase in placebo hair counts they offered neither explanation for this phenomenon nor was the implication of this confounder considered. How such an important observation might have been generated, and its impact on the efficacy of the active treatment was impossible to address in this communication. Identifying potential confounders and their influence on hair counts cannot be ignored in future hair growth efficacy studies. We would suggest before undertaking clinical trials where hair evaluation is an outcome that the evaluation methods be fully validated before the start of the investigation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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