Journal of Dermatology and Clinical Research

Cite this article: Guertin PA (2016) Stricter Regulations and Adaptive Clinical Trial Design for Safer and more Effective Skin Care Products. J Dermatolog Clin Res 4(5): 1086.

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*Corresponding authorPierre A. Guertin, Department of Psychiatry and Neurosciences, University Laval and CHU de Québec, Laval University/CHU de Québec, 2705 Laurier Boulevard, Quebec City, QC, Canada, G1V 4G2; Tel: 418-525-4444 (ext.48831); Email:

Submitted: 06 December 2016

Accepted: 06 December 2016

Published: 07 December 2016

Copyright© 2016 Guertin

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Editorial

Stricter Regulations and Adaptive Clinical Trial Design for Safer and more Effective Skin Care ProductsPierre A. Guertin*Department of Psychiatry and Neurosciences, University Laval and CHU de Québec, Canada

Abstract

Over-the-counter dermatological, skin care and anti-aging creams and gels are not sig-nificantly regulated nor approved by authorities prior to commercialization. Despite increasing public awareness and lobbying campaigns, the Food and Drug Administration (FDA), Health Canada (HC) or the European Medicine Agency (EMA) have not yet proposed stricter rules and laws that would enable safer and more effective industrially manufactured skin care products to be designed, manufactured and sold by sponsors. Ingredients such as aluminum, parabens, fragrances, butylated hydroxyanisole, coal tar dyes, or polyethylene remain extensively used although they clearly dose-dependently vvv both in vitro and in vivo models, cell death, toxicity and carcinogenic activity. Moreover, most currently proposed products do not provide scientific evidence of efficacy in meeting clinical needs. Next-generation skin care products, bound to be acting upon newly unravelled cellular targets for inducing greater efficacy, selectivity and specificity, will hopefully require adoption of heightened standards. The development of adaptive clinical trial designs, in line with the specific needs of this industry, would undoubtedly contribute to reassure and protect patients while providing meaningful safety and efficacy data approvable by competent authorities.

EDITORIALFor obvious safety reasons, drugs, biologics and small-mol-

ecule therapeutics developed as prescription pharmaceutical products against CNS and non-CNS diseases are normally as-sessed and approved by regulatory agencies in U.S., Canada and Europe – FDA, Health Canada, EMA (e.g., http://www.fda.gov/forpatients/approvals/drugs/) [1,2]. During normal drug de-velopment processes, most safety pharmacology and toxicology data are obtained during preclinical tests using whole animals and/or reduced animal models (e.g., cultured cells, plasma, etc.) [3]. If sufficient data are provided and Investigational New Drug (IND) application is approved, enabling subsequent studies in humans (so-called clinical trials) to be authorized by regulatory agencies-that is the clinical studies aimed at gaining additional safety, toxicology, tolerability, pharmacokinetic (clinical phases I-IV) and proof-of-efficacy data in patients (clinical phases II-III) [4]. Specifically, the phase I trial (> 50 healthy volunteers)uses designs such as dose escalation, randomization, placebo-controlled and blind testing to identify dose-dependent adverse events, therapeutic window, toxicology, tolerability, drug-drug interactions, and maximum tolerated dose (MTD), to name a few (www.fda.gov) [4,5]. In larger cohorts (phases II-IV), some of these data remain to be collected for further details about the ef-fects of repeated administration and long-term use. Phase II and III trials are largely about gaining evidence of efficacy-increas-

ingly large cohorts of volunteered patients need to be recruited –the Phase II trial typically seeks the recruitment of 50-150 vol-unteers where as the Phase III may recruit 500-2000 volunteered patients in order to clearly demonstrate statistically the extent to which a drug candidate fulfills the targeted unmet medical need in patients. Phase II and III studies are by far the most expen-sive - up to 2.5 billion dollars according to recent estimates [6] making it unlikely as such to meet the needs and reality of the cosmetic/cosmeceutical industry because of financial reasons. Indeed paying $1,000-10,000 dollars for a new potent therapy may be acceptable for patients with cancer (insurance compan-ies and Medicare) but probably not for individuals experiencing chronic dry skin (xerosis), pruritus or age-related changes and wrinkles [7].

General problematic to overcome - Still today, active ingredients, preservatives and additives for targeted actions, color, odour or over-the-counter chemical stability (shelf-life) and antimicrobial activity (e.g., aluminum, BHA, BHT, coal tar dyes, DEA-related ingredients, dibutyl phthalate, formaldehyde-releasing preservatives, parabens, fragrance, PEG compounds, petrolatum, siloxanes, sodium laureth sulfate, triclosan) remain extensively used in industrially manufactured cosmetics and cosmeceuticals (). Moreover, evidence of efficacy in scientifically sound, clinically-proven tests is generally lacking prior to commercialization [8-13]. In North America and Europe most of

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the skin care products are still approved and marketed without significant regulatory hurdles (albeit the existence in some countries of a short-list of controlled or banned ingredients-e.g., (http://www.hc-sc.gc.ca/cps-spc/cosmet-person/hot-list-critique/hotlist-liste-eng.php). This said, hybrid designs could probably be explored in some conditions (see sections below) for assessing safety and efficacy of less complex products or for products comprising relatively safe compounds [14,15]. This could be of particular interest both for the industry and regulatory agencies given such pivotal data are likely to become a priority for the next-generation cosmetic and cosmeceutical products.

1) Proposable clinical trials for products comprising unknown pharmaceutical or medicinal ingredients–Unknown pharmaceutical ingredients, also referred to as new molecular entities (NMEs), are associated with the stricter rules of development in the pharmaceutical industry. It would be logically inconsistent to have less-strict requirements for cosmetic or cosmeceutical products that comprise at least one NME either of synthetic origin or derived/extracted from complex natural products. Indeed, by definition, NMEs are associated with completely unknown safety and efficacy data. As such a full development path (preclinical studies and phase I-IV clinical trials) is imperative in all cases. Because the costs of standard drug development have skyrocketed in recent years (i.e., from $100 million up to $2.5 billion dollars) [6,7], this would make it unlikely for most sponsor companies attempting to develop safe and potent cosmetic and cosmeceuticals products in this category to comply with the strictest level of requirements [16] except for L’Oréal, Unilever and Procter & Gambles Co. known for having revenues (> 15 billion dollars in revenues in 2015) comparable with those often found in the pharmaceutical industry (statista.com).

2) Proposable clinical trials for products comprising existing pharmaceutical or medicinal ingredients–There are several types of existing pharmaceutical ingredients – some have been used as research tool, but never been tested in humans, while others have been tested in humans by clinicians (physician-sponsored studies) but not regulatory-approved for an indication (e.g., Parkinson’s disease, cancer, etc.) because of insufficient safety and efficacy data. Obviously, those belonging to the former category are associated with little to no safety and toxicology data. Therefore, a full path of development shall be proposed (see section above). However, for those that have already been tested somehow in patients, normally at least some safety and efficacy data should be available. From there, pending upon available data, it may be possible with two series of clinical studies (e.g., a Phase I/IIa and a pivotal Phase III) to obtain the complementary safety and efficacy needed for approval. As an example, Maca powder is currently sold as a natural substance boosting energy and libido. It is authorized in North America and although preclinical efficacy data exists - tests in animals, it has never undergone, in its complex, final powder form, clinical scientifically sound trials (i.e., randomized, placebo/active comparator-controlled, escalating dose study in individuals experiencing libido problems diagnosed by a qualified investigator – that is a physician) [17]. Nonetheless, it has been used by Peruvians for at least 500 years with no reported sign (using surveys) of significant

adverse events or life-threatening complication [17]. A properly-designed Phase I/IIa trial could provide pharmacokinetic, safety and tolerability data, whereas a sufficiently large Phase III trial could potentially demonstrate clearly efficacy and long-term safety upon repeated use.

3) Proposable clinical trials for products comprising ingredients with long history of use–For instance, natural, herbal-derived products that have been used for a long time and for which a bulk of data (safety, tolerability, efficacy) is available (e.g., caffeine for memory impairment problems) although no standard clinical trials have been undertaken. It shall be permitted for such products, if safety and tolerability profiles are positive, to undergo simply a well-designed pivotal phase II/III trial prior to approval (as permitted generally for me-too products or biosimilar products) followed with a post-market surveillance (phase IV) study for further long-term safety and tolerability data upon repeated use. One good example recently published is with green tea against type 2 diabetes-related dyslipidemia. It has been clearly shown in 92 volunteers diagnosed with type 2 diabetes using a randomized, double-blinded, and placebo-controlled pivotal phase II/III trial that green tea safely and potently improve lipid profile and abnormalities compared with controls [18]. Also, green tea, black tea and other teas combined other natural products have recently been found in a pivotal clinical study to safely and potently improve skin moisture and softness in individuals with chronic xerosis [19].

Stricter and legally binding rules and regulations forcing sponsors to conduct clinical trials that seek scientifically sound, clinically-proven data will be determinant for the development of safer and more effective products in the future. As a matter of fact, some legislative changes for natural health products are currently being proposed in Canada (Globe and Mail, Sept 9th, 2016). To remain cost-effective, hybrid study designs shall be permitted in some conditions (i.e., for candidate products such as existing molecules or complex natural products with some history of use or significant safety data) where as shorter, smaller and cost-effective clinical trials shall be authorized pending upon post-market surveillance (so-called phase IV studies) conducted by sponsors for long-term monitoring of safety upon repeated use [20]. Adapting regulations that meet the needs of the cosmeceutical industry shall help obtaining valuable safety and efficacy data prior to approval. Safety pharmacology and tolerability (e.g., vital signs if applicable or relevant side effects for skin care products (e.g., skin allergy, itching, inflamed, redness, swelling, pain, infection, etc.), stability (shelf-life), bacterial testing, range of effective doses (i.e., MTD may be optional if known-molecules with extensive safety data are used),and proven-efficacy upon repeated use and type of administration (e.g., topical) should constitute some of the pivotal data to be provided to the authorities for approval.

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Guertin PA (2016) Stricter Regulations and Adaptive Clinical Trial Design for Safer and more Effective Skin Care Products. J Dermatolog Clin Res 4(5): 1086.

Cite this article

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