Vigro – Mr Knowlton’s substantiation

This is Mr Knowlton’s arguments why Vigro’s claims are justified.

It is essential for readers to appreciate that there are a number of important and valid constraints when evaluating evidence. For example, internal company studies are not given the same value as when published in peer-reviewed publications for obvious reasons: can one believe the company’s data? Was it correctly interpreted? And so on.

A very critical point that readers should consider is this: if one takes on ingredient (proven to work or not) and adds it to a another product which contains a number of ingredients, does the original ingredient still have the exact same efficacy. For example, taking hydrochloric acid (HCl) and adding it to sodium hydroxide (NaOH) and flour in a particular order and dose, may result either in the flour first being denatured by the hydrochloric acid – before the last item is added. However if one adds the first two first before the flour, in the correct does, they react to form water and salt!  [ HCl + NaOH === NaCl + H2O ] 

And adding water to flour gives a different outcome than the other order. In this case, one can predict this.

In complex mixtures, e.g., Vigro, one simply cannot.

 

PO Box 41555
CRAIGHALL
2024

2 March, 2013
Advertising Standards Authority of South Africa

Dear Sir/Madam,

VIGRO / H A STEINMAN / 21666 

I am writing with reference to the complaint made by Dr. Harris Steinman in a letter to the Advertising Standards Authority of South Africa, dated 31 January, 2013, which pertains to the validity of certain claims being made for products sold under the brand name Vigro®, a product range manufactured and distributed in South Africa by Nativa (Pty) Ltd., specifically marketed to address the problems associated with thinning hair. At the outset, and before laying out my credentials to act as an independent expert in this matter, I note that Dr. Steinman submitted a very similar challenge to the ASA in his letter dated 28 November, 2011, when the Vigro® brand was being marketed by PSN Brands (Pty) Ltd. and that matter was subsequently handled under VIGRO/H A STEINMAN/19196.

Whilst I have no intention of reiterating this matter (of which the Directorate is fully aware), it is pertinent to note that although the Directorate initially upheld the complaint, it was subsequently overturned by the ASA Standards Committee, as a result of an appeal against the original ASA Ruling and evidence submitted to the ASA Standards Committee at that time. Notwithstanding the history of this matter, I will be offering an expert opinion in the new challenge (referenced VIGRO/H A STEINMAN/21666) based upon the documentary evidence that I have been provided with by the new Vigro® brand owner, Nativa (Pty) Ltd.

 

I (Cosmetic Solutions) have been requested to provide an independent opinion in respect of the substantiation of the aforesaid claims, based upon scientific data provided to me in confidence by the manufacturer of the active ingredient incorporated in the range in question.

I obtained my degree in Chemistry in 1978. I further hold an accreditation as a Chartered Chemist of the European Union and I am a member of the Royal Society of Chemistry. I have extensive worldwide experience in cosmetic research and development as well as scientific, technical and quality control services relating to cosmetics. I have contributed to numerous scientific publications and held the positions of President of the Society of Cosmetic Scientists of Great Britain and President of the South African Society of Cosmetic Scientists in 1992 and 1999 respectively.

My business (Cosmetic Solutions) provides services that include the formulation and development of new and innovative cosmetic products and advising on quality control, manufacturing and development of cosmetic products.

By virtue of my academic qualifications, experience and background of 28 years in the cosmetic and personal care industries, including clinical studies and trials, I qualify as a credible expert in the relevant field.

I have a comprehensive knowledge of the cosmetic and personal care industries in general and am suitably qualified to express opinions regarding advertising campaigns in these and industries and studies relating to the efficacy of associated products, including the performance of ingredients of these products.

I have been involved in numerous cosmetic, fragrance, homecare and personal care product related matters brought before the ASA in the past and I (Cosmetic Solutions) have previously (in matters such as Harpic Power Plus/Unilever/10982 –September 2008; Dettol Deodorants/B Manning/9239 – 12 July 2007 and Pure Tissue Oil/Bio Oil – 2 November 2006) been accepted by the ASA as an independent and credible expert in these industry categories. Although the products in question have been submitted for registration as complimentary medicines, the nature of the claims being referred to by Dr. Steinman in his complaint to the ASA clearly fall within the realms of hair growth physiology, a scientific discipline that is also encompassed by the field of cosmetic science. Indeed, the matter of whether such products are classified as cosmetics, or complimentary medicines, is not as much an issue focussed on technology design but rather the nature of the claims being made for the products themselves.

That the products concerned may be classified as complimentary medicines is thus not in contention and my attention in this matter is focussed on the scientific substantiation of said claims in the context of the following clauses of the ASA Code of Advertising Practice:

  • Section II, Clause 4.1 – Substantiation
  • Section II Clause 4.2.1 – Misleading Claims

In the context of this case, I have received and examined the following documentation in this matter:

  1. ASA complaint received from Dr HA Steinman dated 31 January, 2013.
  2. A scientific in vitro study on “The Stimulation of the Synthesis of Base membrane Constituents” in dermal papilla cells, provided by the manufacturer of the active ingredients used in the Vigro® product range (Study 1).
  3. A scientific in vivo study (10 human volunteers, over a three month period) on the application of a hair care preparation containing the active ingredient used in the Vigro® product range and its effect on anagen (growth phase), telogen (falling hair) and catagen hair, during the period of testing (Study 2).
  4. A scientific in vivo study (29 human volunteers, over a six month period) on the application of a hair care preparation containing the active ingredient used in the Vigro® product range and its effect on Cumulated Hair Thickness and Density in subjects affected by Androgenetic Alopecia (AGA). This was an independent study conducted at the University Hospital of Giessen and Marburgand and led by Professor Dr. Pia Freyschmidt-Paul a leading and well-recognised scientist in the field of alopecia research (Study 3).

In the current complaint, Dr. Steinman refers to a number of claims being made for Vigro® on the product website and he argues that in every case, for the specific claims in question (which Dr. Steinman has annotated by the use of italics in his complaint), that inadequate substantiation exits. In as much as I will be addressing the substantiation for these claims, it is prudent to list them individually:

  • “….an effective and long lasting solution to thinning hair”
  • “The Vigro® system supports your scalp to re-activate hair growth and thereby helping to maintain the natural balance of hair loss and growth” (There is a note  that Vigro® is not effective against hereditary hair loss)
  • “…with the active ingredient FollcusanTM – shown to assist the scalp in counteracting non-hereditary abnormal hair loss, by helping to reactivate hair cells to promote new hair growth, as well as helping to strengthen weakened hair follicles”
  • ….that assists the scalp to guard against hair loss, promote thicker and to help guard against premature hair loss, promote thicker and stronger hair, as well as providing exceptional nourishment to detangle and smooth your hair

In essence, the substantiation required for all of the above claims, collectively, depends upon the data available to demonstrate that the active ingredient used, “FollicusanTM”, does in fact have the activity claimed for the stimulation of hair growth and prevention of hair loss. I have examined all of the scientific data submitted to me, as referred to above, and from this examination, I have drawn my conclusions from each of the three studies referred to and I would make the following comments:

1. Scientific Study entitled “The Stimulation of the Synthesis of Base membrane Constituents” (in vitro)

  • This study clearly demonstrates that FollicusanTM has a positive influence on the production of ATP in human dermal papilla cells, in a dose-dependent manner, with an increase in ATP of more than 25% at a concentration of 1.6% of the active ingredient, when compared to an untreated control. Since it is well established that the rate of growth of the hair is directly related to the production of ATP in the dermal papilla cells, then it is a clear and logical extrapolation that FollicusanTM would positively influence the growth of new hair. This study clearly demonstrates that Follicusan’ stimulates the proliferation of human dermal papilla cells, in a dose-dependent manner, with an increase in cell proliferation of up to 72% at a concentration of 3.2% of the active ingredient, when compared to an untreated control.
  • This study clearly demonstrates that Follicusan’ stimulates collagen type IV bisynthesis in human dermal papilla cells, in a dose-dependent manner, with an increase in the production of type IV collagen of over 15% at a concentration of 3.2% of the active ingredient, when compared to an untreated control.
  • This study clearly demonstrates that Follicusan’ stimulates heperan sulphate proteoglycan biosynthesis in human dermal papilla cells, in a dose-dependent manner, with an increase in heperan sulphate proteoglycan of up to 21% at a concentration of 3.2% of the active ingredient, when compared to an untreated control.
  • It should be noted that all of the in vitro evaluation studies were conducted using a concentration of either 1.6% or 3.2% of Follicusan’ (the active ingredient), whereas the concentration used in the Vigro® system is 5.0%, significantly higher than the concentrations studied. As a result of this observation, it is logical to conclude that the benefits obtained when using Vigro® would be similar to those demonstrated in the studies at the very least and, in practice, probably better because of the concentration dependence on activity.
  • In his letter of complaint, Dr. Steinman claims that these studies have “no relevance” because the trial does not use human subjects. Respectfully, this opinion is simplistic and erroneous and it is commonly recognised in scientific communities worldwide that data generated by in vitro studies of this type can be used to accurately predict in vivo behaviour in humans, provided (i) that the study is relevant to human physiology and (ii) that the active ingredient in question can be effectively delivered to the site or organ in the human body that was the subject of the in vitro study, in this case the human dermal papilla cells. The relevance to actual human physiology is unquestionable in this case, as all of the in vitro studies have incorporated the use of human dermal papilla cells. That Follicusan’ contained in the Vigro® system can be effectively delivered to the human papilla cells on the scalp, is a topic that I will address in detail later in this opinion.

 

  • 2. Scientific Study using 10 Human Volunteers (in vivo)
    • In this study 10 human volunteers (5 males and 5 females) using a hair gel containing 5.0% Follicusan’ resulted in an average reduction of 30% telogen (falling) hair for 80% of the male subjects taking part an average reduction of 34% telogen for all of the female participants. Moreover for the male subjects, there was an average increase of 22% anagen (growth phase) hair in 60% of the panellists and for the female subjects an average increase of 11% anagen hair, for all participants taking part in the study.

3.         Scientific Study entitled “Influence of the preparation CLR05 (Follicusan’) on Cumulated HairThickness and Density in Women affected by Androgenetic Alopecia (ACA)

  • This study, conducted at the University Hospital of Giessen and Marburgand and led by Professor Dr. Pia Freyschmidt-Paul, a leading and well-recognised scientist in the field of alopecia research, determined the effectiveness of Follicusan’ both in the stimulation of hair growth and the counteraction of hair loss.
  • In this study, a topically applied hair preparation containing 5.0% Follicusan’ was applied to the scalps of 29 female volunteers subjects (24 subjects completed the study) suffering from Androgenetic Alopecia (AGP). This study demonstrated that hair density, cumulated hair thickness and terminal hair density did not suffer significant change over a 6 month period, in. In other words, the maintenance of hair density, cumulative hair thickness and terminal hair thickness has effectively retarded the rate at which the hair thins, in subjects suffering from this condition.
  • In his letter of complaint, Dr. Steinman raises concerns over the fact that only female volunteers were used in this study and that the number of panelists completing the study, a total of 24 subjects, is insufficient to draw statistically significant conclusions from the study results.
  • With respect to the extrapolation of the results obtained on female volunteers and their validity for men, it is important to note that the condition being suffered by the panelists was Androgenetic Alopecia, a condition caused by male hormones such as testosterone. The pathophysiology for cell biological processes such as dermal papilla cell function are the same for both men and women and in the case of subjects suffering from Androgenetic Alopecia, the functioning of those cells is signficantly affected by the same processes, irrespective of gender. In light of this observation, it is reasonable for the benefits observed in this study to be equally applicable for men and women. Two scientific papers are provided with this opinion in support of the view herein expressed:
    • M Fiurášková et al: Pathobiology of Androgenetic Alopecia, Biomedical Papers 147(1), 3741 (2003) – See Study 4
    • M Bienova et al: Androgenetic alopecia and current methods of treatment, Acta Dermatoven APA Vol 14, 2005, No 1 – See Study 5
    • On the subject of the number of subjects used in this study, 24 partcipants, Dr. Steinman’s allegation that this is insufficient to obtain statistical signficance is incorrect. In the case of conventional assessment techniques, 24 subjects may conceivably not provide statistical significance, although panel sizes as small as 15 subjects can provide a high degree of statistical significance, depending upon the type of study and the assessement techniques being used. In this particular study a special assessment technique known as TrichoScan® was utilised to obtain the measurements on volunteers. TrichoScan® is a highly sensitive and scientifically-validated method to quantify hair growth in individuals and use of of this methodology allows a smaller study population size to yield statistically significant results, which would not be the case when using conventional assessment methodologies. A scientific paper is provided with this opinion in support of the use of the TrichoScan® technique, where panel sizes as small as 10 subjects can yield significant results:
      • J Gassmueller et al: Validation of TrichoScan® technology as a fully-automated tool for evaluation of hair growth parameters, European Journal of Dermatology, 19 (3): 224-31 (2009) – See Study 6
      • In conclusion therefore, the use of Tricoscan® technology in this study has enable the dataset obtained on 24 female subjects to yield scientifically valid and statistically significant results.

 

  • 4. The Case for Product Specific Substantiation

* Throughout this complaint, and in those preceeding it, there is the matter of what constitutes “product specific substantiation” and the fact that the excipient design in the Vigro® system differs from the excipient designs used in the various scientific studies on FollicusanTM discussed in this opinion, has been a matter of contention for Dr. Steinman throughout. In a previous communication to the ASA Directorate, dated 26 May, 2012, I provided the following opinion on this matter :

* “…it is trite that the Directorate requires unequivocal and product-specific substantiation…” but the issue in question is exactly what constitutes “product‑specific substantiation”?

With all due respect to the Directorate, the interpretation of “product-specific substantiation” that each and every product is required to be tested in its entirety is impractical and unworkable; neither does this requirement fall in line with internationally-accepted standards for product claim substantiation in any other part of the world. Even in the case of generic drugs, once the efficacy of a dose form has been clinically substantiated, it is commonly accepted that the drug will be effective in a wide variety of excipients and delivery systems, provided that there is no scientific reason to believe that the excipient design, or delivery system, would positively of negatively affect the proven efficacy of the drug. The requirement to fully retest the drug in every possible combination of excipient/delivery system, to generate “product-specific” substantiation data, would be impractical and unworkable and, furthermore, is not required by the international community to support the efficacy of that drug. In summary then, I would submit that the interpretation of the term “product-specific”, actually relates to whether or not the data available (assuming that this data unequivocally demonstrates the efficacy of the “active” concerned) may be extrapolated to the marketed product in which the same “active” has been used, assuming that the concentration of the “active” is the same, or greater than that used to generate the data, and that the excipient design would have no influence, positively or negatively, on the efficacy of the “active” in question. In this context, what may otherwise be classified as “generic” data can be regarded as true of the product in question, hence fulfilling the definition of “product-specific” substantiation.

 

  • In the case of the studies discussed in this opinion, the clinical benefits of Follicusan’ have been proven at concentrations less than, or equal to, the concentration of this ingredient used in the Vigro® system. Assuming that the excipient design of the Vigro® system will exert neither a synergistic or antagonistic effect on the effect of the active ingredient Follicusan’, then in my professional opinion the clinical efficacy of Follicusan’, and hence the Vigro® system, has been adequately substantiated by the studies discussed in this opinion and, as such, the claims being called into question by Dr. Steinman are adequately substantiated.
  • Notwithstanding the debate on “product specific substantiation”, there is a significant factor in this particular case that has been overlooked by Dr. Steinman and that is the method by which the delivery of the active ingredient Follicusan’ to its target, the dermal papilla cells, is achieved. As previously stated, for the data obtained in the studies discussed in this opinion to be relevant to the performance of the Vigro® system, there are two conditions that must prevail; (i) that the study is relevant to human physiology and (ii) that the active ingredient in question can be effectively delivered to the site or oragn in the human body that was the subject of the in vitro study, in this case the human dermal papilla cells.
  • That the studies are relevant to human physiology are without question, as in the case of in vitro studies only human dermal papilla cells have been utilised to evlaute the performance of Follicusan’ and in the in vivo studies this requirement is automatically met. It is the method by which Follicusan’ is delivered to its target, the dermal papilla cells of the scalp, that is pivotal in determining the validity of the studies reviewed in this opinion, as adequate substantiation of the claims being challenged by Dr. Steinman.
  • In the case of a skin care product for example, the delivery of the active ingredient(s) takes place by a number of different mechanisms and in this case it is extremely important to consider the excipient design in delivering the active ingredient(s) to their intended target. In the case of the Vigro® Bio-Tonic, the component of the Vigro® system that delivers the therapeutic levels of Follicusan’, the product is applied directly to the scalp and delivery is achieved through direct follicular penetration. In other words, when the Vigro® Bio-Tonic is applied to the scalp in the prescribed manner it can immediately penetrate the hair follicules which are open on the surface of the scalp, thus giving the product immediate access to the dermal papilla cells found at the base of the open follicule. In these circumstances, where the product containing the active ingredient can directly access its target, the dermal papilla cells, the excipient design is irrelevant, as it has little or no effect on the delivery of the active ingredient itself. As such, Dr. Steinman’s concerns about excipient design and the effect that it has on the activity of FollicusanTM are in this case without foundation.

* Direct follicular penetration is a well-studied physiological principal, as is evidenced by extracts taken from the following scientific papers (copies attached):

  • F Knorr et al. : Follicular transport route – Research progress and future perspectives, European Journal of Pharmaceutics and Biopharmaceutics 71 (2009) 173180 – See Study 7
  • “…may be especially relevant for hydrophilic and high molecular weight molecules, as well as by particle-based drug delivery systems”
  • “…changes in the differentiation pattern along the follicular duct, the follicle possesses distinct characteristics which favour penetration”
  • ” The hair follicles in contrast represent efficient long-term reservoirs (up to 10 days) for topically applied substances, as their depletion occurs only through the slow processes of sebum production and hair growth”
  • Otberg et al.: Follicular Penetration of Topically Applied Caffeine via a Shampoo Formulation, Skin Pharmacol Physiol, 20 (2007):195198 – See Study 8
  • “Absorption through the hair follicles and relevant caffeine levels in the blood were already found 5 min after topical application, whereas comparable levels could only be obtained after 20 min when caffeine permeated only through the stratum corneum of the interfollicular epidermis”
  • “The hair follicle epithelium shows an epidermal differentiation in the infundibulum. The epithelium of the uppermost parts shows no difference to the interfollicular epidermis; in the lower parts of the infundibular epithelium, cproviding exceptional nourishment to detangle and smooth your hair”orneocytes are smaller and appear crumbly. This part of the follicular epithelium can be seen as an incomplete barrier for topically applied substances”

o H Wosicka et al: Targeting to the hair follicles: Current status and potential, Journal of Dermatological Science 57 (2010) 83–89 – See Study 9

[spoiler title=”Comment” style=”fancy”]It is well known that very few compounds are absorbed through the skin. Therefore one cannot claim that because caffeine is absorbed through the skin (or follicles), that other substances such as Follcusan in Vigro can achieve the same.[/spoiler]

[spoiler title=”Comment” style=”fancy”]This study concludes very clearly: “There is also a variety of formulation aspects (vehicles, carriers, penetration enhancers) that have to be taken into consideration while creating an effective hair follicle targeting system.” In other words, how does one know for a fact that adding Follcusan into the Vigro mix will result in the claimed effects without checking whether any of the other ingredients alter any of the ingredient effects. This can only be an absolute guess – science and proof does NOT work this way![/spoiler]

  • “For the scalp and face, the combined areas of follicular openings can be as much as 10% of the total skin area”
  • “Many studies suggest that the follicular pathway, in contrast to the conventional transdermal pathway, is especially favorable for highly hydrophilic and high-molecular weight substances, as well as particle-based drug delivery systems”
  • “For instance, 40-nm nanoparticles, which were shown to cross the skin barrier via hair follicles, may be an example of how particle based systems can be used to transdermally deliver active vaccine compounds”
  • “It is important to emphasize the role of massage (following application) on follicular penetration as many studies use it to improve follicular penetration.”

In summary, and in consideration of all of the scientific studies submitted to me, it is my professional opinion that the claims:

  • “….an effective and long lasting solution to thinning hair”
  • “The Vigro® system supports your scalp to re-activate hair growth and thereby helping to maintain the natural balance of hair loss and growth”
  • “…with the active ingredient FollcusanTM – shown to assist the scalp in counteracting non-hereditary abnormal hair loss, by helping to reactivate hair cells to promote new hair growth, as well as helping to strengthen weakened hair follicles”
  • ….that assists the scalp to guard against hair loss, promote thicker and to help guard against premature hair loss, promote thicker and stronger hair, as well as providing exceptional nourishment to detangle and smooth your hair

are fully substantiated by the studies reviewed in this opinion and referred to above.

 

It is therefore my contention that the following clauses of the ASA Code of Advertising Practice:

  • Section II, Clause 4.1 – Substantiation
  • Section II Clause 4.2.1 – Misleading Claims

have not been breached in any way and that the claims currently being made may continue to be used.

Yours sincerely,

 

John L Knowlton C.Chem, MRSC, Dip. Cos. Sci. (GB) Independent Consultant to the Cosmetic Industry

 

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