Are Healthcare Antiseptics Toxic to Staff and Patients?

FDA's Proposed Rule to Establish Safety and Efficacy of Antiseptics

Laura A. Stokowski, RN, MS; Theresa Michele, MD


June 16, 2015

Editorial Collaboration

Medscape &

Editor's Note:
The US Food and Drug Administration (FDA) recently issued a proposed rule pertaining to the safety and effectiveness of over-the-counter (OTC) antiseptic products used in healthcare settings. Products included in the rule are "healthcare antiseptics" (healthcare personnel hand washes, healthcare personnel hand rubs, surgical hand scrubs, surgical hand rubs, and patient preoperative skin preparations). "Washes" are products that are rinsed off with water, and "rubs" are leave-on products.

The FDA is seeking additional data from manufacturers on the safety and effectiveness of the active ingredients in these products, including absorption data, potential hormonal effects, and possible bacterial resistance. Their purpose is to establish the long-term safety of daily, repeated exposure to the active ingredients of these antiseptic products.

Recently, Medscape spoke with Theresa Michele, MD, Director of the Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research at the FDA, about the proposed rule and the implications for healthcare professionals and patients.

Medscape: Why did the FDA decide to look into the safety and effectiveness of antiseptics now? How does the current action fit in the broader context of the FDA's oversight of antiseptics?

Dr Michele: The FDA issued a proposal on healthcare antiseptics in 1994, and since then much has changed. Our safety standards, our ability to detect and measure antiseptics in the body, and our scientific knowledge about the impact of widespread antiseptic use have all evolved since that time.

For the past several years, the FDA has been very actively engaged on this issue. This is part of an ongoing process for us, in which we are reviewing all of the antiseptic OTC ingredients that are found in healthcare antiseptics marketed under the OTC monograph (OTC drug review). In 2005 and again in 2014, the FDA sought the advice of an FDA advisory committee made up of outside scientists and medical experts. The 2005 advisory committee primarily focused on efficacy requirements, and the 2014 committee primarily focused on safety requirements.

In the proposed rule, we modified the effectiveness study design on the basis of recommendations from the 2005 advisory committee and laid out the safety data that the 2014 advisory committee agreed are needed for these products.

Medscape: Healthcare providers have been using these products rather liberally for many years. Although it was understood that there might be limitations to their effectiveness depending on how they were used, it was assumed that they were generally safe to use. Have new data prompted you to question their safety, or is the present work developing from an abundance of caution to make sure that the ingredients in these products meet new standards for safety?

Dr Michele: The first thing to emphasize is that the FDA has not determined that these products are unsafe. What we have determined is that data gaps exist that need to be filled for us to make a definitive finding that healthcare antiseptics containing these ingredients are generally recognized as safe and effective (GRASE).

Emerging science suggests that at least for some of the ingredients, systemic exposure may be higher than we previously thought.[1,2,3,4,5] We used to think that when you put these ingredients on the skin, that is where they stayed. It was believed that none of the ingredients actually got into the bloodstream. Now we know that at least for some of the ingredients, it may be possible for them to enter the bloodstream after skin administration.

The second thing that we have learned is that owing to concern about healthcare-associated infections, healthcare workers are using these products much more frequently than they used to. As an intensive care unit physician, I can tell you that we use these products up to 100 times every shift—every time you enter a patient's room, and every time you exit a patient's room. Thus, even small amounts of absorption might add up over the long term. That's what we are looking at.

We are primarily concerned about how much people are being exposed to over the course of a working lifetime of use of these ingredients, and what are the potential adverse events that could occur as a result of this exposure.

Medscape: Let's talk about the products that are affected by the rule. Is it correct that you are focusing on 29 OTC ingredients and ingredient combinations already in use in antiseptic products, and this does not include those in consumer products? If companies introduce new OTC antiseptics any time in the future, will they be subject to the same proof of GRASE?

Dr Michele: The OTC space is sometimes confusing, even for those of us who work in it. OTC products are regulated in one of two ways: through the OTC drug review (monograph) process, and by the new drug application (NDA) pathway.

Active ingredients that were on the market in the OTC setting before 1972, when the OTC drug review was established, may be regulated as ingredients under the monograph system. OTC monographs are a kind of rule book that says if a product containing an ingredient could be GRASE, then manufacturers can formulate that ingredient in any way that meets the other conditions of the monograph. It's an ingredient- and condition-based system. There are probably many hundreds of healthcare antiseptic products out there that are marketed under the monograph, but there are only 29 active ingredients in those products.

The NDA pathway is the same as for prescription drugs, where we look at each drug product individually. Healthcare antiseptics that are marketed under the NDA process do not come under this proposed rule. Consumer products also do not fall under this proposed rule.

Medscape: What are the most common ingredients in these OTC antiseptics? Are the ingredients different from those found in healthcare antiseptics that fall under the NDA system?

Dr Michele: The two most common active ingredients among OTC monograph antiseptics used in healthcare are alcohol (ethanol) and povidone-iodine. The most common active ingredient in healthcare antiseptics that fall under the NDA process is chlorhexidine.

Medscape: What type of evidence are you asking for to determine the effectiveness of the OTC healthcare antiseptics?

Dr Michele: It is very difficult to conduct clinical outcome studies in healthcare settings to show effectiveness of healthcare antiseptics. Therefore, a generally recognized as effective (GRAE) determination for an active ingredient in a healthcare antiseptic should be supported by an adequate characterization of the antimicrobial activity of the ingredient through both in vitro testing and in vivo clinical simulation testing. Our criteria for effectiveness are based on the premise that bacterial reductions can be demonstrated using tests that simulate conditions of actual use for each category of OTC healthcare antiseptic product and that those reductions are reflective of bacterial reductions that would be achieved during real-world use.

Medscape: You have announced that manufacturers must submit safety data on these products within 1 year. Do you believe that manufacturers already have data on long-term consequences, especially in vulnerable populations (eg, pregnant or breastfeeding women)? Otherwise, wouldn't it take longer than a year to collect data on the long-term effects of antiseptic exposure?

Dr Michele: In some cases, we think the manufacturers may have the data already, in which case they can just send it in. Some of the data that we are asking for can be procured in a short timeframe (for example, the absorption data). However, some of the long-term animal studies to look at the potential to cause cancer, for example, will take more time, and in those cases, we would be open to the possibility of working with manufacturers who are willing to commit to doing the needed studies.

Medscape: The proposed rule also requests data from manufacturers on the potential development of antimicrobial resistance from long-term use of these products. Is this just a theoretical concern, or has evidence come to light to indicate that resistance does develop?

Dr Michele: We have some very limited laboratory data that have shown some cross-resistance between antiseptics and antibiotics.[6,7,8,9] However, there is nothing definitive at this point in time, and that's why we are asking for additional data. We don't know anything about use and resistance in a real-world healthcare environment.

Medscape: You have said that the exposure of healthcare workers to the ingredients in these OTC antiseptics is higher than previously thought. Have any studies been conducted in healthcare workers yet to quantify this exposure? Do you know, or are you just assuming, that healthcare workers in certain settings (eg, intensive care, surgery) have higher exposures?

Dr Michele: We really don't have very good data to quantify exposure, and that is why we are asking for it. One of the pieces of data that we have asked for is a maximal use trial, which is conducted in a small number of human subjects who will use the product in the maximum expected way that a healthcare worker would. Then we measure blood levels of the active ingredients. It's a fairly straightforward study used to determine how much systemic exposure occurs.

Medscape: What do we know about the factors that might increase transdermal absorption of active ingredients in antiseptics? Is it primarily frequency- or time-related, or does the volume of product used by the healthcare worker have any impact on absorption?

Dr Michele: Several different elements can affect systemic exposure. You have named a few of them—the duration of exposure and the frequency of use. Other factors include the surface area of the exposed skin, the age of the person using the antiseptic, and the formulation used. That is why we are asking for the maximal use trial.

Medscape: Is it possible that one outcome of this process is that we will be returning to the days of soap and water for hand hygiene in healthcare? Do you expect manufacturers to remove their products from the market?

Dr Michele: No, we don't anticipate that outcome. In addition, we have NDA products that are approved for these uses, and those products will not go away. For some of the ingredients—such as alcohol, one of the ingredients used most frequently—the FDA anticipates that the data gaps will be fairly easy to fill, and we expect that manufacturers will conduct the studies needed to provide the requested information.

Medscape: You have said that this is ultimately a question of risks and benefits. Healthcare workers understand why antiseptics are used and presumably, now that this issue has been brought to the forefront, accept that they are exposed to some degree of risk in using them. If it is ultimately determined that some or all of these ingredients are toxic to healthcare workers, the risks of exposure of healthcare workers will have to be weighed against the risks for transmission of infection to the patient. How much risk should healthcare workers have to assume for the benefit of patients? Who will make that decision?

Dr Michele: That is the key question that healthcare workers will be asking. One of the things about the paradigm that we are looking at is that it allows us to assess both the risks and benefits, more so than we are able to do with the information that we have right now. In general, the benefits of a product are determined by its efficacy, and the risks of a product are determined by its safety profile. We are looking at both under this proposed rule. In some cases, I suspect that it will be very clear-cut; in other cases, it may not be as clear-cut and may open the opportunity for public discussion.

The same risk/benefit analysis applies to all NDAs. This is something that the FDA does every day. The message to healthcare workers right now needs to be that they should continue to use these products. These are part of the standard of care in infection control, and we have no data at this point telling us that these products are clearly unsafe.

Medscape: What else would you like healthcare providers to know about the proposed rule?

Dr Michele: The most important point to emphasize is that although there are some data gaps, healthcare antiseptics are an important component of infection control. Healthcare personnel should continue to use these products consistent with applicable guidelines while we are gathering and analyzing the data. And stay tuned—we intend to publish a final monograph in 2018.