Regulatory Aspects of Hand Hygiene
Hand sanitizers are not cosmetics, they are over-the-counter (OTC) topical drugs and they are regulated as such by the FDA. It is important at this juncture to consider the regulation of antimicrobial topical products. In 2005, the FDA’s Nonprescription Drug Advisory Committee concluded that the existing in vitro data failed to correlate bacterial log reduction studies with reduced infection. In 2013, the FDA became concerned about the proliferation of cleansing products that were making antibacterial claims, often without sufficient substantiation. This concern represented the culmination of scrutiny of products by the American Medical Association, the U.S. Congress and the FDA.
In 2002, the Council on Scientific Affairs of the American Medical Association (AMA) reported that despite the substantial increase in the use of antimicrobial ingredients in consumer products, there was no data to support the efficacy or necessity of antimicrobial agents in such products. Moreover, a number of studies suggested that the common use of these antimicrobial agents increased acquired bacterial resistance, and that they could predispose bacteria to resistance against therapeutic antibiotics.
Considering the available data and the critical nature of the antibiotic resistance problem, it was prudent to avoid the use of antimicrobial agents in consumer products. The AMA recommended, “the use of common antimicrobials for which acquired bacterial resistance has been demonstrated should be discontinued in consumer products unless data emerge to conclusively show that such resistance has no effect on public health, and that such products are effective at preventing infection. Ultimately, antibiotic resistance must be controlled through judicious use of antibiotics by health care professionals and the public.97
Triclosan-resistant strains of Escherichia coli and Salmonella enterica were identified during the first decade of the 21st century.98-100 Concerns about triclosan go back to at least 1978, when the FDA was in the process of constructing a Final Tentative Monograph for health care antiseptic drug products and responded to comments that “triclosan has been implicated in Pseudomonas contamination because it is primarily effective against Gram-positive bacteria, has limited in vitro and in vivo activity against Gram-negative bacteria, and no activity against Pseudomonas (43 FR 1210 at 1232).”101 Such limitation in the spectrum of antimicrobial activity could indicate that an antimicrobial active could promote antibiotic resistance.102
In the years leading up to 2010, products containing triclosan came under intense media and Congressional scrutiny with allegations that it accumulated in body fat and had the potential for endocrine disruption. Additionally, there were concerns that residual triclosan could lead to the emergence of strains of antibiotic-resistant and antibiotic-tolerant pathogenic microorganisms.
Prompted by his Congressional sub-committee, in December 2010, Rep. Ed Markey, Chairman of the Energy and Environment Subcommittee of the Energy and Commerce Committee, submitted letters of concern to the FDA and Environmental Protection Agency (EPA) about their lack of urgency in effectively regulating this chemical.103 That same year, Rep. Louise M. Slaughter asked the FDA to ban triclosan due to the hazards the chemical poses, including antibiotic resistance and potential health problems leading to higher health care costs.
The FDA responded by acknowledging that soaps containing triclosan offered no additional benefit over regular soap and water, and that the data raised valid concerns about the health effects of repetitive daily human exposure to these antiseptic ingredients. It also announced plans to address the use of triclosan in cosmetics or other products. Further, the FDA also expressed concern about the development of antibiotic resistance from using antibacterial products and about triclosan’s potential long-term health effects.104 These actions added urgency to the regulation of “antimicrobial” claims for cosmetics and personal care products. Subsequently, in 2017 and 2019, the FDA issued its Final New Rules for Handwash Antiseptic products and for Antiseptic Hand Rub products, respectively.
The FDA’s reasons for a Final New Rule for Antiseptic Drug products were:
• A mere cleansing product is different from a cleansing product with antibacterial claims;
• FDA cited a lack of evidence for safety and effectiveness of antiseptic rubs;
• The average consumer cannot discern whether or not an antiseptic product is safe and effective, and this needs to be declared by distinctive labeling; and
• Firms are better-equipped than consumers to know about the health advantages, safety and efficacy of their products.
Antiseptic washes: As noted, the final rule for consumer antiseptic washes intended to be rinsed off became effective in 2017.105 The FDA found that, of some 22 active ingredients, only three—benzalkonium chloride, benzethonium chloride and chloroxylenol—were considered to possibly be generally recognized as safe and effective (GRASE) and that more information and data was required. The decision on these three actives was therefore deferred to allow more time to generate sufficient data and information for final judgment by the OTC Review Committee.
Insufficient data was submitted to demonstrate the other 19 active ingredients provided additional infection-reducing benefits, compared with plain soap and water. The was also insufficient data to establish the safety of repeated daily exposure to these actives. These ingredients are therefore not GRASE, and under Section 502 of the Federal Food, Drug and Cosmetic Act, products containing these actives are misbranded drugs. These 19 actives include: clofucarban, fluoroslan, hexachlorophene, hexylresorcinol, iodophors, methylbenzethonium chloride, phenol, secondary amyltricresols, sodium oxychlorosene, tribromsalan, triclocarban, triclosan and triple dye.
The FDA rendered the following actives to be ineligible for inclusion in the OTC monograph system for antiseptic wash products, and required approval through the New Drug Application process: alcohol (ethyl alcohol), benzalkonium cetyl phosphate, cetylpyridinium chloride, chlorhexidine gluconate, isopropyl alcohol, polyhexamethylene biguanide, salicylic acid, sodium hypochlorite, tea tree oil and the combination of potassium vegetable oil, phosphate sequestering agent and triethanolamine. The FDA further singled out triclosan and triclocarban as actives that could pose some health risks, such as alterations in the thyroid, reproductive growth and the developmental systems of neonatal and adolescent animals.
Antiseptic rub products: The Final Rule for antiseptic rub products became effective on April 13, 2020.106 The FDA considers antiseptic rubs as products for use when soap and water are not available. The final rule applies to liquids, foams, gels and wipes intended to reduce the number of bacteria on the skin and not intended to be rinsed off with water. It applies to consumer products and not professional or institutional products. The intent of the rule was to remove harmful antiseptic active ingredients—and it did remove 28 such ingredients, leaving only three actives eligible for consideration: ethyl alcohol, isopropanol and benzalkonium chloride. Regulatory action on the three eligible actives is delayed, subject to the generation of required GRAS and GRAE data. The 28 ineligible active antimicrobial actives would require a New Drug Application in order to be considered for approval by the FDA. Among the 28 ineligible actives are: benzethonium chloride, chloroxylenol, chlorhexidine gluconate, cloflucarban, fluorosalan, hexachlorophene, hexylresorcinol, iodine complex, phenol and triclosan.
Alcohol antiseptic hand rubs were recategorized from Category I to Category III, wherein FDA categories for monograph processes for OTC drugs are:
• Category I: generally recognized as safe and effective for the claimed therapeutic indication;
• Category II: not generally recognized as safe and effective or unacceptable indications;
• Category III: insufficient data available to permit final classification.
Therefore, eligible alcohol antiseptic hand rubs were classified as having “insufficient data to meet safety requirements.” The new requirements for the approval of alcohol-based antiseptic hand rubs and their move from Category III back to Category I include the following; notably, the FDA estimates the cost of conducting the recommended clinical trials and changes will amount to ~$2 million.
• Bacterial log reduction studies that show the superiority of the test product to the negative control by 1.5 log, wherein the negative control is the product vehicle or a saline solution;
• Products must show a non-inferiority of the test product to active control by 0.5 log. The active control must be an FDA-approved antiseptic rub. As an aside, there is only one FDA-approved antiseptic rub that has successfully passed through an NDA and that is an antiseptic pre-surgical hand rub intended for use by health care personnelb. This antiseptic hand rub comprises 61% w/w ethyl alcohol and 1% w/w chlorhexidine;
• The new rule mandates the required log reductions must be met within 5 min after a single rub;
• Human pharmacokinetic studies must be conducted under maximal usage levels to generate information on systemic exposure and determine if the products meet GRAS requirements; and
• The potential for the development of antibiotic-resistant bacteria must be evaluated. For ethyl alcohol and isopropanol, sufficient data has already been provided to assess the risk of antiseptic resistance and antibiotic cross-resistance; more information is required for benzalkonium chloride.
The efficacy of alcohol antiseptic hand rubs does not correlate with their alcohol content and is formulation-dependent. There is thus is a need to understand the mechanistic principles of hand rubs in order to predict the efficacy of formulations, and to detail and standardize testing protocols. In this regard, it has been disclosed that under a certain testing protocol, the previously described pre-surgical hand rubb does not meet the required 3 log reduction on Day 5, whereas a product containing 70% ethyl alcohol as the only active ingredient does meet the required 3 log reduction.107
Some insight into the FDA’s reclassification of hand rubs can be discerned by reading the agency’s analyses that support the final rule,108 and by considering that the FDA has relied upon the works of the pre-eminent and informed microbiologist Stuart Levy, M.D., of Tufts University (S. Levy 1938-2019). Levy taught the following concepts:109
• We exist in a bacterial world, not bacteria in ours;
• We believe we can rid ourselves of bacteria but we cannot; and
• We must control pathogens when they cause disease and not engage in a full-fledged war against the entire microbial world. “We should make peace with them.”
Like Strachan, Levy also warned about the hygiene hypothesis. Following these teachings, the FDA expressed concerns including:
• The consumer’s and industry’s response to superbugs; i.e., the rise of multi-drug resistant microorganisms that are resistant to antibiotics;
• The increase in consumer products with antibacterial claims—from just a few dozen in the 1990s to more than 700 by 2001—and need to ensure their efficacy and safety. In relation, the concern that residuals from such products could lead to the evolution of drug-resistant strains of pathogens. In this respect, it should be noted that alcohol, bleaches and peroxides leave no such residuals.
• The use of such antiseptic products progressing from occasional to regular daily use by consumers. The FDA seeks additional evidence confirming that this increased exposure is safe. In relation, improved analytical methods have the potential to shine new light on the effects of long-term exposure. The agency cites five references in this respect that could provide insights.
Alcohol absorption: In connection with exposure, the FDA cites an Australian paper focused on the potential for alcohol absorption into the skin and negative effects on probationary drivers or regarding religious taboos.110 In the study, subjects applied a 61% alcohol rub product to their hands every 2 min for one hour, then had their breath tested for alcohol by HPLC. Results were: 60% of subjects tested negative, 30% registered alcohol on their breaths for 2 min and 10%, for 7 min. After 10 min, there was no detectable alcohol on the breath of any of the subjects. A traffic breathalyzer did not detect any alcohol at any time. This study concluded the fear of losing a driver’s license from alcohol rubs was not valid.
The FDA also cited a paper that showed that the alcohol absorbed from a hand rub product was approximately one-tenth of that ingested in a single alcoholic beverage.111 Finally, in the case of what is referred to as the “Purell Defense,” DUI offenders (including one U.S. Congressman) plead that the alcohol detected on their breath came from the use of hand-sanitizing gels. A paper by Wigmore, however, proved the absorption of alcohol from sanitizing gel was not forensically significant.112
It would appear there is little scientific support for concerns about the toxicity of alcohol hand rubs due to skin absorption. Moreover, the total exposure of hand rub consumers to alcohol is minuscule compared with the total exposure of those who consume alcoholic beverages in the United States (see Figure 1).
The Hand Rub Market, IP and Litigation
The hand rub market is dominated by alcohol products (see Figure 2), and while there are many small businesses in this sector, 84% of all antiseptic rub products are shipped by just four large firms, each with more than 1,000 employees (see Figure 3). These companies spend significant amounts of time and money on FDA new drug applications (NDA), so they should have intellectual property (IP) provisions in the form of patents to protect their technology from intrusion by generics, which can lower the incentive to invest in clinical testing.
The original patents for hand sanitizer have expired and current intellectual property activity in this space appears to be directed to hardware and formulations for ease of dosing, which might prove difficult to police; and sporicidal formulations directed to a specialized market segment. Even with a demonstrated need in the era of COVID-19, however, there could be enough market uncertainty to negate the incentive to conduct clinical testing to meet these new requirements set forth by the FDA. It may therefore be reasonable to enquire whether it is in the interest of public health to impose such financial burdens, disclosed above, on individual companies under such future market uncertainty.
However, in accordance with the tentative final monograph, the FDA issued a warning letter to GOJO Industries113 over its well-known Purell product cautioning the company, “claims that PURELL Healthcare Advanced Hand Sanitizers are effective in preventing disease or infection from pathogens such as Ebola, MRSA, VRE, norovirus, flu and Candida auris, and in preventing the spread of infection, go beyond merely describing the general intended use of a topical antiseptic as set forth in the above-referenced relevant rulemakings.” Furthermore, “claiming hand sanitizers are effective in reducing illness or disease-related student and teacher absenteeism also go beyond merely describing the general intended use of a topical antiseptic as set forth in the above-referenced relevant rulemakings. Such claims are not described in any OTC final rule.”
In connection, litigation has resulted from the language in the FDA Final Rule and disputed product claims. Purell’s label states the product “can kill 99.9% of illness-causing germs,” but a lawsuit against Purell alleges, “these claims lack scientific basis rendering the affirmative misrepresentations misleading.”114
In another class-action lawsuit, David, Lara, Haas and others versus Vi-Jon and GERM-X, the complaint states, “on January 17, 2020, the [FDA] issued a warning letter to Purell … regarding its representations that its alcohol-based hand sanitizer—which is nearly identical to Germ-X—could prevent the flu and other viruses. The FDA stated that it is not aware of ‘any adequate and well-controlled studies’ supporting that representation.”
The FDA warning letter also points to GOJO’s website, which states: “[A]re Purell Hand Sanitizer products effective against the flu? The FDA does not allow hand sanitizer brands to make viral claims but from a scientific perspective, influenza is an enveloped virus. Enveloped viruses in general are easily killed or inactivated by alcohol. The World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) are recommending the use of alcohol-based hand sanitizer as a preventive measure for flu prevention.” It is legitimate to ask whether lawsuits like these are in the interest of the common good, and this question is especially relevant at a time when the need is for good public health practices during a pandemic.
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