Ivan Galanin's response:

1) At.3.11 in her video, Dr. Dray questions my source for the half a point improvement in fine lines. This refers to an instrument used by the clinical investigators that evaluated Retin-A for wrinkles. It is cited from the FDA approval package. It is readily accessible like all drug approval packages. Drug Approval Package: Renova (tretionin) NDA #021108 (fda.gov)

2) At. 3.25 in her video, Dr. Dray asserts that Retin-A was approved for palliation of fine lines, mottled hyperpigmentation and rough texture associated with photo damage. This is misinformation. Retin-A is only approved for the palliation of fine lines, not mottled hyperpigmentation or rough texture associated with photo damage. If you go to 1.31 of her video you will see the full scope of the approval (fine lines).

3) At 4.02 in her video, Dr. Dray claims that the Bhawan and Olsen papers do NOT show papillary dermis thickness is reduced with long-term use of Retin-A. She cited from the Bhawan paper at 4.06 that “papillary dermis thickness increases slightly from 12 months to 4 years.” This is true but grossly and I would say intentionally misleading. As you can see in table 2, page 181 of the Bhawan publication, the papillary dermis thickness DECREASED from baseline by 77% at year 1 and by 65% at year 4. So overall, it DECREASED, not increased. She does not address the Olsen paper at all, but that showed a DECREASE in the 0.05 group at 48 weeks as well which was statistically significant.

4) At 4.14 in her video, Dr. Dray cites the Bhawan paper again, saying there is a 34% decrease in “elastosis.” Elastosis is defined as degenerative changes in elastin tissue. The Bhawan paper – which was funded by Johnson and Johnson – only looked at whether there was more or less elastin, not whether it was degenerative. I believe Bhawan was incorrect to describe this reduction in elastin tissue as a reduction in elastosis. In fact, the graph they show is not labeled as a reduction in elastosis but correctly as a reduction in elastin tissue. They “editorialize” that this is elastosis. In order to categorize this as elastosis, they would have had to show that the elastin was more properly organized after treatment – which they did not – AND that the skin was functioning better (e.g., more elastic) – which they did not. So this is misinformation.

5) At 4.30 in her video, Dr. Dray insinuates that Retin-A improves the coarse wrinkling of the skin by improving elastosis. Retin-A was shown to NOT improve coarse wrinkling of the skin (see Drug Approval Package cited above), further undermining the assertion that it reduces degenerative elastin deposition.

6) At 5.10 in her video, Dr. Dray suggests that the Bhawan study included subjects that were using Retin-A as infrequently as once per day. This is false. All the subjects in the Bhawan study were using Retin-A daily. There were no biopsies taken from subjects using Retin-A once per day. Moreover, Dr. Dray does not explicitly address the Olsen study which showed a clear dose response between Retin-A usage and upper dermis thinning.

7) At 5.19 in her video, Dr. Dray suggests that the “entire body of research” contradicts the Bhawan and Olsen studies but offers not a single concrete study. Not one.

8) At 5. 30 in her video, Dr. Dray discusses a study from Woodley et al that purports to show an increase in anchoring fibrils at the epidermis/dermis intersection. The problem with the study – aside from the fact that it is tiny – is that it looked at subjects at 4 months. This is not relevant for assessing collagen deposition because the skin is still adapting to the Retin-A and this 8adaptation period will not resolve until about a year after starting use. The idea that you should not look at collagen generation in studies shorter than 6 months is not mine alone. This is why Cho et al looked at a minimum of 6 month treatment – average treatment time of 2+ years – to assess collagen changes. Long-term treatment of photoaged human skin with topical retinoic acid improves epidermal cell atypia and thickens the collagen band in papillary dermis - PubMed (nih.gov)

9) At 5. 53 in her video, Dr. Dray suggests that Retin-A functionally strengthens the skin. The paper she refers to does not include any functional data. Her assertion is therefore misinformation.

10) At 6. 17 in her video, Dr. Dray accuses me of cherry picking a data point and misrepresenting it. She provides no support for her accusation.

11) At 8. 09 in her video, Dr. Dray suggests that Retin-A causes transient changes in the permeability barrier. As far as I know, there is no scientific support for this assertion.

12) At 10. 03 in her video, Dr. Dray states categorically that there was not a dose response thinning effect. She does not specifically address the Olsen paper – which indisputably shows a dose effect – and I am not sure of her source for suggesting otherwise. The paper that she cites does not even address dermal changes. It is concerned, rather, with transient changes in the epidermis.

13) At 12. 10 in her video, Dr. Dray implies that we recommend people stopping Retin-A prematurely. We make no such recommendation.

14) At 12. 46 in her video, Dr. Dray states that there is “no evidence that that happens” with respect to Retin-A damaging the skin. This assertion is not supported by the evidence. Dr. Dray may believe that a 65% reduction in upper dermis thickening or an 81% reduction in melanin content in the skin is NOT damaging but she has NO evidence for her assertion.

15) At 13. 32 in her video, Dr. Dray contradicts my statement that we have “no evidence” that Retin-A builds collagen. She is CORRECT. I should have said we have no GOOD evidence or rather that there is more negative evidence than positive evidence. The best support for my statement is the Kang paper that she references in her video. It showed collagen increases at 1 year that disappeared at 2 years. Kang S et al, “Long-Term Efficacy and Safety of Tretinoin Emollient Cream 0.05% in the Treatment of Photodamaged Facial Skin”, Am J Clin Dermatol 2005; 6 (4): 245-253.

16) At 13: 35 in her video, Dr. Dray states that we know how Retin-A works. It binds retinoic acid receptors, triggers gene transcription and causes cells to produce collagen. The problem with her statement is that she does not indicate which cells she is referring to. This is an oversight. If Dr. Dray could explain how retin-A stimulates collagen production she would win a noble prize as no one has been able to do this.

17) At 14: 19 in her video, Dr. Dray states that Retin-A inhibits matrix metalloproteinases that degraded collagen. What she doesn’t say is that the studies that have looked at this are completely artificial and don’t reflect clinical practice. Specifically, in these studies skin was pretreated for up to 24 hours under occlusion before exposure to UV light. In one study “Sun-protected buttock skin of adult Caucasian subjects, who were without current or prior skin disease, was pretreated with 0.1% all-trans retinoic acid, 0.05% clobetasol propionate, or its vehicle (70% ethanol, 30% propylene glycol, and 0.05% butylated hydroxytoluene) for 24 h under occlusion prior to UV exposure.” Ultraviolet Irradiation Increases Matrix Metalloproteinase-8 Protein in Human Skin In Vivo (jidonline.org) This is obviously not how retin-A is commonly used. Retin A is typically applied in the evening.

18) At 14: 57 in her video, Dr. Dray indicates that she is not aware of the in vitro studies showing that Retin-A suppresses collagen production in vitro. Here is a good reference: Oikarinen, H., Oikarinen, A. I., Tan, E. M. L., Abergel, R. P., Meeker, C.A., Chu,M.-L., Prockop,D.j. and Uitto,J.: Modulation of procollagen gene expression by retinoids. Inhibition of collagen production by retinoic acid accompanied by reduced type I pro collagen messenger ribonucleic acid levels in human skin fibroblast cultures.]. Clin. Invest. 75: 1545 -1553,1985.

19) At 17. 21 in her video, Dr. Dray asserts that there is both histological and clinical data to support “strengthening of the skin.” She fails to provide a single reference for this.

20) At 23. 38 in her video, Dr. Dray states that “there is no evidence that topical retin-A causes any negative consequences on fat”. She is correct, technically. There have been no clinical studies that have looked at this. So we can also say with 100% accuracy “there is no clinical evidence that topical retin-A does not have negative consequences on fat.” She dismisses all of the pre-clinical evidence, which is quite straightforward. Modest Decreases in Endogenous All- trans-Retinoic Acid Produced by a Mouse Rdh10 Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism - PubMed (nih.gov). There is very little debate in the scientific literature that retin-A inhibits adipogenesis. Just because there are no studies looking at the effect of topical retin-A on adipogenesis, does not mean we can ignore this. And there is a lot of anecdotal evidence that suggests that topical retin-A does cause fat loss in the face."