OVER-THE-COUNTER TOPICALS: ASSESSING THE NEED FOR TESTING AND LABEL CLAIMS AGAINST VIRUSES SYMPOSIUM MINUTES

Transcription

1 ASTM Post-Conference Workshop OVER-THE-COUNTER TOPICALS: ASSESSING THE NEED FOR TESTING AND LABEL CLAIMS AGAINST VIRUSES SYMPOSIUM MINUTES Held on: Friday, October 8, 2004 Omni Shoreham Hotel, Washington, D.C. Sponsored by ASTM International, West Conshohocken, PA ASTM Post-Conference Workshop October 8, 2004 Page 1 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

2 ASTM Post-Conference Workshop OVER-THE-COUNTER TOPICALS: ASSESSING THE NEED FOR TESTING AND LABEL CLAIMS AGAINST VIRUSES Friday, 08 Oct 04, 8:30 a.m.-3:30 pm. -- Omni Shoreham Hotel, Washington, D.C. Sponsored by ASTM International, West Conshohocken, PA 8:30 8:40 Welcome and Opening Remarks Dr. John Mitchell, Co-Chair, ASTM Subcommittee E Session Conveners: Dr. Ward Billhimer, Proctor and Gamble Co., and Ms. Donna Suchmann, MICROBIOTEST, INC. 8:40 9:20 Current Issues in Hand Hygiene in Infection Control Presented by Dr. John M. Boyce, Professor and Chief of Infectious Diseases, Department of Medicine, Hospital of Saint Raphael, 1450 Chapel Street, New Haven, CT. 9:20 10:00 The Role of Hands in the Spread of Nosocomial Viral Infections Presented by Dr. Syed A. Sattar, Director, Centre for Research on Environmental Microbiology (CREM), University of Ottawa, Ottawa, Ontario, Canada. 10:00 10:15 Coffee Break Session Conveners: Mr. Mike Dolan, GOJO Industries, Inc., Dr. Lawton Seal, Healthpoint, Ltd., and Ms. Chris Turner, Metrex Corp. 10:15 10:45 The Survival, Transfer and Inactivation of Foodborne Viruses: Summary of Recent Research in Canada Presented by Dr. Sabah Bidawid, Manager of Research, Health Canada, Ottawa, Ontario, Canada. 10:45 11:15 Methods for Testing the Activity of Topicals Against Viruses: U.S. and Global Perspectives Presented by Dr. M. Khalid Ijaz, Vice President, MICROBIOTEST, Inc., Sterling, VA, and Affiliate Professor, George Mason University, Fairfax, VA. 11:15 11:45 U.S. Food and Drug Administration s Guidelines on Hand Antisepsis Procedures for Food Handlers Presented by Dr. David Acheson, Chief Medical Officer, CFSAN, FDA, Washington, D.C. 11:45 1:15 Lunch Break Session Conveners: Dr. Jerry Newman, STERIS Corporation, and Dr. Albert Sheldon, Antibiotic and Antiseptic Consultants, Inc. 1:15 1:45 U.S. Food and Drug Administration s Perspective on Regulating Label Claims of Activity against Viruses Presented by Dr. Nilamber Biswal, Division of Anti-Viral Drug Products, FDA, Washington, D.C. 1:45 2:15 The OTC Drug Monograph Process Ms. Debbie Lumpkins, Division of Over-the-Counter Drug Products, FDA, Washington, D.C. 2:15 3:15 General Discussion Discussion Moderators: Ms. Kathy Baxter, Co-Chair, ASTM Subcommittee E 35.15, and Dr. Daryl Paulson, BioScience Laboratories, Inc. Expert Panel: Dr. David Acheson, Dr. Shamim Ansari, Dr. Sabah Bidawid, Dr. Ward Billhimer, Dr. Nilamber Biswal, Dr. John Boyce, Dr. Peter Coderre, Ms. Debbie Lumpkins, Dr. M. Khalid Ijaz, Mr. Dan Klein, Dr. David Macinga, Dr. Jerry Newman, Dr. Julian O Rear, Dr. Syed Sattar, Dr. Lawton Seal, Dr. Albert Sheldon, Ms. Donna Suchmann, Ms. Chris Turner, and Ms. Carla Weisend. 3:15 3:30 Closing Remarks and Thanks Dr. M. Khalid Ijaz, Chair, Organizing Committee for ASTM E Anti-Viral Task Force ASTM Post-Conference Workshop October 8, 2004 Page 2 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

3 WELCOME AND OPENING REMARKS Dr. John Mitchell, Co-Chair, ASTM Subcommittee E35.15 Dr. Mitchell welcomed the attendees to the ASTM Post Conference Symposium on Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses and explained the objective of the symposium. The speakers would present data that 1) show the need for topical products to remove viruses from the hands; 2) explain the necessity of such products in the marketplace and in industry; and 3) review the test methods that are available to demonstrate that the products inactivate viruses. Dr. Mitchell noted that several individuals from various regulatory agencies were present at the symposium and represented the following branches of the FDA: Center for Food Safety and Applied Nutrition (CFSAN), the Division of Anti-Viral Drug Products and the Division of Over-the Counter Drug Products. The goal of the symposium is to open a dialog between industry and the regulatory agencies and to begin to answer the following questions: 1) what kind of data are needed to show the regulatory agencies that these topical products work; and 2) how do we move this process further and provide products for use in the healthcare and food industries? Dr. Mitchell concluded by thanking the following people and companies for their support and financial sponsorship of this symposium: Daniel Smith, ASTM E35 Manager Dr. M. Khalid Ijaz, Chair for ASTM E35.15 Anti-Viral Task Force ASTM International, Sponsor Bioscience Laboratories, Inc., Sponsor GOJO Industries, Inc., Sponsor Healthpoint, Ltd., Sponsor Hill-Top Research, Inc., Sponsor MICROBIOTEST, Inc., Sponsor Proctor and Gamble Co., Sponsor STERIS Corporation, Sponsor ASTM Post-Conference Workshop October 8, 2004 Page 3 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

4 CURRENT ISSUES IN HAND HYGIENE IN INFECTION CONTROL Dr. John Boyce, Professor and Chief of Infectious Diseases, Department of Medicine, Hospital of Saint Raphael, New Haven, CT Dr. Boyce presented his views on this topic as an infectious disease specialist. He began by providing an overview of the annual impact of healthcare-associated infections in the US and listed the major sites of nosocomial infections for both medical and surgical patients. Fungal infections, particularly Candida sp., are becoming more common. Bacteria account for 90-95% and viruses for 5-10% of the important healthcare-associated pathogens; in children, viruses cause 32% of nosocomial infections. Rhinovirus and Influenza virus (in winter) account for the majority of viral respiratory infections. These viruses can be spread by direct or indirect contact, droplets or airborne transmission. Dr. Boyce provided statistics on the number of childhood hospitalizations and deaths from Respiratory Syncytial Virus (RSV), as well as the modes of nosocomial transmission. In a prospective study of RSV transmission in a hospital nursery, investigators found that droplet and indirect contact transmission were responsible for the observed nosocomial infections. In a separate study, it was noted that opportunities for self-inoculation of respiratory viruses occur commonly among medical personnel. Rhinovirus is shed in large amounts from infected individuals and at least 40% of them contaminate their hands with the virus. Rhinovirus can survive for several hours on skin and on environmental surfaces. The experimental transmission of Rhinovirus was investigated and found to occur primarily through direct contact (hand to hand transmission) and then by large droplets. In the SARS epidemic, the virus often was spread in hospitals, and nosocomial infection accounted for 72% and 55% of the cases in Toronto and Taiwan, respectively. In 20% of the cases (44% in Toronto), healthcare workers were affected. Transmission of the virus occurred primarily through respiratory droplets and direct contact. Dr. Boyce discussed viruses implicated in gastroenteritis infections. In one study, diarrhea was the third most common nosocomial infection in children with approximately 56% of the episodes having an identifiable cause (Rotavirus and Adenovirus being the most identified viruses). Viral diarrhea was most common in children less than two years of age. The incidence and impact of Rotavirus, Norovirus and Astrovirus was presented, as well as their modes of transmission. Several viruses including Herpes simplex, Varicella-zoster and Cytomegalovirus can be transmitted from patients to healthcare workers. Although an important cause of foodborne infection, Hepatitis A rarely causes nosocomial outbreaks affecting healthcare workers. The bloodborne pathogens, Hepatitis B and C and HIV, however, can have serious life-long effects on healthcare workers who have been exposed to them via blood or body fluids contaminated with blood. Dr. Boyce finished his overview of the different viruses causing infections by mentioning viral hemorrhagic fever agents and smallpox as possible bioterrorism agents. ASTM Post-Conference Workshop October 8, 2004 Page 4 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

5 Dr. Boyce concluded his presentation with a discussion on the importance of handwashing. Many of the viruses mentioned in his earlier slides are transmitted from one person to another through direct contact; as a result, the hands of healthcare workers easily can become contaminated. In a 20-year observational study ( ), it was noted that the average rate of handwashing compliance of healthcare workers was approximately 40%, and no trend towards improvement is apparent. Several reasons exist as to why handwashing compliance is low. Factors such as high workloads, job category, weekday schedules, and working in an ICU are associated with poor adherence to handwashing procedures. Dr. Boyce reviewed a recommended soap and water handwashing policy and questioned whether it is really practical when compared to the time required for an alcoholic hand disinfection procedure. In addition, poor access to sinks and handwashing facilities also adversely affect compliance. Irritant contact dermatitis due to frequent handwashing is another significant deterrent. In one prospective study, it was shown that soap and water dried the hands of nurses to a greater extent than an alcohol gel. Dr. Boyce emphasized that the extent to which a formulation is tolerated by healthcare workers is critical; if the product kills the pathogens but damages/dries the hands, it will not be used. During seven hospital-wide surveys, investigators noted percent compliance in hospitals increased when hand disinfection using alcohol hand gels was implemented. In the same study, it was found that as hand hygiene increased, the incidence of nosocomial infections decreased. Alcohol-based hand rubs have several advantages compared to traditional soap and water handwashing. The rubs require less time to use, are more accessible than sinks, result in less skin irritation and dryness, are more effective in reducing bacteria on hands, and have led to improved hand hygiene practices. Dr. Boyce briefly mentioned the Hand Hygiene Guideline published in Morbidity and Mortality Weekly Review in This was an extensive literature review with input from the FDA. The exposure to healthcare workers to a variety of viral pathogens warranted a discussion of antiviral activity of hand antiseptic agents, which included information about in vitro evidence of antiviral activity and results of in vivo testing using the fingerpad method. Several unresolved issues still exist. Multiple strategies are required to improve adherence to hand hygiene policies but which are the most effective? The level of efficacy needed to effectively reduce transmission of healthcare-associated pathogens is not known. The issue of persistent activity has not been addressed. Finally, compared to EN standards, current US regulations appear to make development of formulations containing more than one active agent very expensive. ASTM Post-Conference Workshop October 8, 2004 Page 5 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

6 DISCUSSION Dr. Al Sheldon: You mentioned the effects of viruses in clinical medicine and the effects of antiseptics in reducing nosocomial infections. In the papers you presented, did any of the authors conduct a subset analysis on viral infection rates? Dr. Boyce: None of the authors commented on what proportions of infections were viral. These studies require significant resources and funding and need to be conducted over a period of several months. Dr. Jerry Newman: You correlated pathogens to irritated skin. Are the data clear enough to be accepted as dogma for bacteria. Is this also true for viruses? Dr. Boyce: Individuals with dermatitis have been shown to have increased bacterial colonization. There have been outbreaks of nosocomial methicillin-resistant Staphylococcus aureus infections when healthcare workers have colonization of S. aureus as well as dermatitis. There is good epidemiological evidence for bacterial colonization and dermatitis, but I m not sure if dermatitis affects colonization of hands by viruses. ASTM Post-Conference Workshop October 8, 2004 Page 6 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

7 THE ROLE OF HANDS IN THE SPREAD OF NOSOCOMIAL VIRAL INFECTIONS Dr. Syed Sattar, Director, Centre for Research on Environmental Microbiology (CREM), University of Ottawa, Ontario, Canada Dr. Sattar focused his presentation on the following topics: impact of infections on health, explanation of nosocomial infections, a description of viruses and the roles of hands in their spread, and the future of antiviral products. A literature review of human pathogens has shown that 1415 pathogens have been identified. Bacteria account for 538 of the known pathogens and viruses for 217; fungi, protozoa and helminthes account for the rest. The routes of spread of >200 of these pathogens are unknown. In the past 30 years, >40 new pathogens have been discovered and include SARS and Noroviruses. Globally, infectious diseases cause >32% of the 56 million fatalities/year and lead to 19% of visits to physicians/year. Nosocomial infections are those that occur in a patient in whom the infection was not present or incubating at the time of admission and also include occupational infections among staff. After reviewing the basic structure of a virus, Dr. Sattar discussed the importance of viruses as pathogens. Viruses are major causes of mortality and morbidity, and in the U.S., they account for 5% of nosocomial cases, with about 32% occurring in pediatric settings. Viruses are common in respiratory and enteric infections (diarrhea, influenza), and many of the newly identified pathogens are viruses. They also play a significant role in foodborne illnesses (e.g., Hepatitis A and Norwalk virus). There have been no serious breakthroughs in vaccines/drugs against viruses, and, due to undesirable side effects, the rotavirus vaccine was taken off the market. Since there are so many viral strains and the immune response is short-lived, the option of producing a vaccine against some viruses is not feasible. Viruses are beginning to show resistance to drugs. With immunosuppressive drugs being used more often, patients are showing increased susceptibility to nosocomial viral infections and reactivation of latent viruses. The health impact of viruses is increasing. Viruses have been implicated in chronic conditions such as arteriosclerosis, arthritis and exacerbation of asthma. Hepatitis B and C infections can result in hepatocellular carcinoma. In polymicrobic diseases, ~15% of acute otitis media cases are the result of a mixture of bacteria and viruses. In one study, it was found that human adenovirus injected into monkeys resulted in weight gain (obesity). Viruses may trigger specific behaviors and cause psychiatric disorders (e.g., bornavirus). Finally, the appearance of delayed damage several years after viral infection can occur. Examples include genital cancers (papillomavirus), congenital malformations (rubella virus) and hepatocellular carcinoma (Hepatitis B and C). Dr. Sattar reviewed how viruses could be spread in the healthcare setting. Hands can become contaminated with viruses through contact with: clothes and other fabrics, body secretions/excretions, animals, medical devices, water, food, soil, clinical materials, other hands and body surfaces and fomites/environmental surfaces. After artificially inoculating human hands with viruses, Dr. Sattar observed that many viruses survive on ASTM Post-Conference Workshop October 8, 2004 Page 7 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

8 the hands after one hour. After 60 minutes, approximately 40% of the inoculated Coronovirus 229E (surrogate for SARS) are still viable. Although viruses are not part of the body s normal microflora, they do have relevance. There is low relevance for pre-operative skin preparations and surgical scrubs. High relevance occurs in hospitals, nursing home and daycare, food preparation and serving establishments, home care and domestic settings. The non-enveloped viruses of importance include: Adenovirus, Astrovirus, Calicivirus, Enterovirus, Hepatitis A, Papillomavirus, Rhinovirus and Rotavirus. Dr. Sattar reviewed the status of antiviral products in the U.S. In the Tentative Final Monograph (TFM), no mention is made of viruses. Public workshops were held in 1994 and the CTFA/SDA filed a citizen s petition in In 2004, a letter was sent to Dr. L.M. Crawford, Acting Commissioner of FDA, stating that antiviral products should be included in the monograph. To generate discussion on this issue, this ASTM symposium is being held. The Canadians have issued a draft guidance document and are now registering alcohol hand preparations. The following recommendations were made. The FDA should revisit the issue of label claims against viruses for formulations used in nosocomial and food-handling settings. There is a need for field studies to demonstrate product effectiveness. Decisions made by the FDA should be in line with other national and international jurisdictions. DISCUSSION Dr. Jerry Newman: Viruses are not part of our normal flora. Is there a theoretical positioning that viruses may survive longer on damaged skin? Dr. Sattar: There is no evidence. However, individuals with damaged skin may have increased percutaneous exposure to viruses. People with cracked/damaged skin may become infected instead. Dr. Curt White: Viruses are not part of our normal flora but can they be part of our persistent flora? Dr. Sattar: Yes. For example, a certain proportion (10%) of individuals with Hepatitis B become consistently chronically infected and can become a source of infection to others. Shingles is an example of delayed damage and these individuals become a source of virus for younger children. ASTM Post-Conference Workshop October 8, 2004 Page 8 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

9 THE SURVIVAL, TRANSFER, AND INACTIVATION OF FOODBORNE VIRUSES: SUMMARY OF RECENT RESEARCH IN CANADA Dr. Sabah Bidawid, Manager of Research, Health Canada, Ottawa, Ontario, Canada Dr. Bidawid began his presentation with an overview of the organizational structure of Health Canada. The Research division is responsible for supporting regulations and policy setting and his talk focused specifically on foodborne viruses. The topics covered included foodborne viruses, food contamination, food handlers and virus spread, and intervention and control. Viruses do not multiply in food and only a few particles (10-100) are needed to cause infection. They are stable at cold temperatures, resistant to low ph, gastric enzymes, heat (60 o C/1 hr) and chlorine but are sensitive to heat (85 o C/1.5 min), UV and high pressure. The viruses that contaminate food and water are Norwalk- and -like viruses (NLV), Hepatitis A, Rotavirus, Poliovirus, Astrovirus, Coronavirus, Hepatitis E and enteric Adenovirus. There are 38.6 million total foodborne illnesses annually and 80% of these are due to viruses. Caliciviruses and Hepatitis A are responsible for 47% of these viral infections. Transmission of foodborne illness is through the fecal-oral route (person-to person and food and food handlers), airborne particles and fomites. Foodborne outbreaks can occur in a variety of setting such as restaurants, senior homes, nurseries, daycare centers, cruise ships and at home. The foods that become contaminated are also varied and include shellfish, salads, fruits, water, sandwiches, and bakery products. Of 348 outbreaks of NLV, 39% were foodborne. Numerous factors contribute to foodborne outbreaks. Food can become contaminated at the origin or cross contaminated by food handlers. Lack of proper hygiene facilities and improper food handling (cooking, hot holding and storage) can lead to outbreaks. There is also intra- and inter-familial spread. Enteric viruses in tap water, on aluminum surfaces or on vegetables can survive for months, especially at cooler temperatures. Many viruses survive on the hands after one hour. Food handlers have poor personal hygiene, and over 50% of observations in full service restaurants are out of compliance. Dr. Bidawid presented his findings on survival of feline Calicivirus on foods (berries, lettuce, ham) and stainless steel discs. At 4 o C, the virus survives for about eight days but at room temperature, survival is decreased. Hepatitis A inoculated on lettuce can be recovered up to 12 days. Data from virus cross-contamination studies were discussed also. Fingerpads were inoculated with Hepatitis A and feline Calicivirus and then they touched ham, a metal disc or lettuce. The percentages of viruses recovered from the foods/surfaces were 46%, 13% and 18%, respectively. In a second study, the foods and steel disc were contaminated with the viruses and then were touched by the subjects. The recovery from the hands was between 6% and 14%. In related transfer interruption studies, subjects fingerpads again were inoculated with the viruses. Before touching the food and metal disc, the subjects washed their hands with water, water and soap, or alcohol (75% liquid, 62% gel). The percentage of ASTM Post-Conference Workshop October 8, 2004 Page 9 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

10 organisms recovered from the food and surface was significantly reduced (3.4%) with all interventions. With increasing time, the two ethanol-based products exponentially reduced the viral titer. Currently, there has been an increase in market share of antibacterial and antiviral hand products. They are convenient, safe, fast acting and environmentally friendly for use between handwashings and can interrupt the spread of viruses. They have been gaining increasing acceptance in the U.S. and Canada, but there are no regulations to govern antiviral claims. Methods to test antiseptics against viruses are available. Food handlers play an important role in cross-contamination and contribute to the spread of viruses. Control measures consist of education, adequate food preparation practices, exclusion of ill food handlers from work, vaccination and adequate hygienic practices and facilities, including handwashing and antisepsis. Health Canada recently developed a food and environmental virology network to obtain real-time information on viral outbreaks and to link in with other similar networks. DISCUSSION Due to time constraints, there was no discussion. ASTM Post-Conference Workshop October 8, 2004 Page 10 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

11 U.S. FOOD AND DRUG ADMINISTRATION S GUIDELINES ON HAND ANTISEPSIS PROCEDURES FOR FOOD HANDLERS Dr. David Acheson, Chief Medical Officer, Mark Hepp, Consumer Safety Officer, and Captain Wendy Fanaselle, Consumer Safety Officer, Center for Food Safety and Applied Nutrition, FDA, Washington D.C. Dr. Acheson began the presentation by reviewing the different divisions of the FDA and introducing the other two speakers from CFSAN. He discussed what the Food Code represents and its intent. The Food Code is a uniform system of regulation that provides for safe food service and food that is protected and unadulterated. The Code is designed to minimize foodborne illnesses and is followed by state, territorial and local regulatory food agencies. It provides these jurisdictions with a scientifically sound and legal basis for regulating the retail food industry. Five key interventions are included in the Food Code: Demonstration of knowledge, employee health, time/temperature, hands as a vehicle of contamination, and consumer advisory. The five key foodborne illness risk factors are poor personal hygiene, improper food holding temperatures and inadequate cooking, contaminated equipment and food from unsafe sources. The Food Code interventions to control the contamination of ready-to-eat (RTE) foods by food workers are 1) exclusion and restriction of ill workers, 2) handwashing practices as described in the Code, and 3) no bare hand contact with the RTE foods. Dr. Acheson listed the viral and bacterial pathogens often transmitted by food contaminated by infected persons. The two leading viruses were Norovirus and Hepatitis A virus. Norovirus is reported as the single most common cause of gastroenteritis in the western world and accounts for 66.6% of the all foodborne illnesses in the U.S. The virus is highly infectious and very few viral particles are needed to cause illness. Captain Fanaselle discussed the control of foodborne illness pathogen transmission on the hands, with the focus on viruses contaminating RTE foods. Several problems exist in controlling Norovirus. The virus cannot be cultured and the only source is from sick individuals. No universally accepted surrogate exists, although FeCV-F9 has been widely studied. Virus inactivation for Norovirus was found to be similar to FeCV-F9. The challenges for Norovirus are twofold: a universally recognized surrogate is required and clinically relevant reduction levels need to be determined. Improper or lack of handwashing is a serious problem in retail and food service, and the hands play two different roles in foodborne illness caused by contamination of food. The hands are a source of contamination and a vehicle of contamination. In one study by De Witt, et al. using E. coli as an indicator, it was concluded that infected individuals shedding at high levels will have high hand contamination levels, even after handwashing. Captain Fanaselle reviewed the handwashing procedure described in the Food Code. The three stages of handwashing are scrub, rinse and dry. During the scrubbing stage with a cleaning compound, vigorous friction is the most important element in removing ASTM Post-Conference Workshop October 8, 2004 Page 11 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

12 transients. The scrub should be seconds long with soap; to remove soil, and water that is at least 100 o F. The rinse should be under a strong velocity and volume of running water. Hands should be thoroughly dried with heated air, disposable towels or a continuous clean towel system. Each stage of the procedure is important, and the scientific literatures shows that proper handwashing will result in 2-3 log reductions of transient bacteria and a 2 log reduction of viruses. Although one of the interventions of the food code is no bare hand contact of RTE foods, there are several limitations. Utensils such as gloves, tissue paper or tongs are required. Food handlers need to be educated on their proper use and how to choose the appropriate utensil. Certain procedures, such as peeling shrimp, are difficult without the use of bare hands. Glove integrity can be an issue, as is alternatives for individuals with latex allergies. Although 13% of gloves have failures, it has been found that for 77% of the time, gloves with leaks still prevented hand contamination. In addition, the bacterial transfer rate through food service gloves is only 0.01% compared to 10% for washed hands without gloves. Hand antiseptics/sanitizers are allowed after handwashing but cannot be used as an alternative to handwashing for retail and food service workers. Several limitations exist for alcohol-based hand sanitizers in the food service industry. They are impacted by soil and moisture and neutralized by protein. Hand sanitizers have a limited effect on foodborne virus, and one study found incomplete inactivation of Norovirus with 70% ethanol. Hand antiseptics/sanitizers are considered a drug by the FDA and require approval through an OCT monograph, NDA approval process or as an indirect food additive. Dr. Hepp concluded the presentation with a discussion of food additives. A food additive is any substance that reasonably expected to become a component of food as a result of its intended use, if such use is not generally recognized as safe. The Section 409 Safety Review entails an evaluation of the probable consumption of the food additive, the cumulative effects of such additives in the diet, and safety factors recognized as appropriate for the use of animal experimentation data. Dr. Hepp then reviewed when a tolerance must be set. The technical effects of topical products were presented. There is no intended effect in or on food; these products are used to control microbes on humans. Since the Center for Drug Evaluation and Research (CDER) has explicit authority for such effects, CFSAN advises a consultation with the FDA for topical antimicrobial active ingredients. As of this date, CFSAN had not given any approvals. DISCUSSION Due to time constraints, there was no discussion. ASTM Post-Conference Workshop October 8, 2004 Page 12 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

13 METHODS FOR TESTING THE ACTIVITY OF TOPICALS AGAINST VIRUSES: U.S. AND GLOBAL PERSPECTIVES Dr. M. Khalid Ijaz, Vice President, MICROBIOTEST Inc., Sterling, VA and Affiliate Professor, George Mason University, Fairfax, VA Dr. Ijaz began his presentation with a historical perspective of viruses as major etiological agents of infectious diseases in the past 30 years. Predisposing factors include global travel and mass movements, human demographics and behavior, and viral genome changes. Hands play an important role in the spread of many viral infections, and proper handwashing has been shown to interrupt the spread of viruses. There are several major factors involved in testing the antiviral activity of handwash and handrub agents. In vitro carrier testing should be used only as a screen. For in vivo evaluation, subjects should be selected based on strict inclusion/exclusion criteria and after giving informed consent. The selected method should be reproducible and quantitative with precise log reductions calculated. The contact time between the skin and virus should be realistic (10-20 seconds), and a soil load should be included in the viral suspension. Appropriate viruses should be used as surrogates, and a virucida procedure with known effectiveness against the test virus should be used to decontaminate hands after testing is complete. Topical products can be tested in vitro using suspension and carrier tests, in vivo with human subjects or animals, or ex vivo with animal or human tissue. Viruses are able to survive on environmental surfaces. For example BVDV, a surrogate for HCV with an organic load of 10%, takes approximately 24 hours for a 50% reduction in the virus to occur. When the organic load was increased to 95%, the survival rate increased to three days. BVDV (surrogate for HCV) and rhinovirus are able to survive on the fingerpads of adults 20 minutes after inoculation. The in vivo testing of hygienic handwashing agents employing viruses can be performed with the whole-hand, fingertip or fingerpad methods. Two ASTM standard test methods exist for evaluation of hand antiseptics against viruses: E2011 (whole-hand) and E1838 (fingerpads). Several weaknesses inherent in the whole-hand test procedure were discussed.. There is the potential for virus wash-off during the pre- and post-treatment water rinse. A concentration step is needed since the volume of the recovery medium is too large. Each subject can be used to test only one product/control against one virus, and incorporation of a paper towel-drying step makes it difficult to assess the true effectiveness of the handwash agent. Although the entire hand is inoculated, only the fingertips are sampled, and post-test decontamination of the whole hand is difficult to achieve. The fingertip method has most of the same limitations as the whole-hand method. Dr. Ijaz reviewed the various steps in conducting the fingerpad method. The advantages of this method are numerous and include a known volume of test inoculum placed on a well-defined test area, a known volume of test product applied to the test area, and the control and reference solutions being included in the same test along with the test formulation. Virus loss due to mechanical removal, in situ inactivation and posttreatment water rinsing can be distinguished. The method can be used with ASTM Post-Conference Workshop October 8, 2004 Page 13 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

14 conventional or handrub formulations and is suitable for work with all major classes of microorganisms. The results obtained with this method are comparable to those from the whole-hand procedure. MICROBIOTEST had submitted a protocol based on this method that can be viewed at FDA docket ( 0183H_emc pdf) Dr. Ijaz discussed the relevance of alcohol-based antiseptics against viruses and listed several viruses as potential surrogates. He concluded with a list of issues that need to be resolved. These included the acceptability of surrogates, harmonization of test methods, performance criteria for handwash and handrub products, and the importance of residual activity. DISCUSSION Due to time constraints, there was no discussion. ASTM Post-Conference Workshop October 8, 2004 Page 14 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

15 U.S. FOOD AND DRUG ADMINISTRATION S PERSPECTIVE ON REGULATING LABEL CLAIMS OF ACTIVITY AGAINST VIRUSES Dr. Nilamber Biswal, Microbiologist, Division of Anti-Viral Drug Products, FDA, Washington, D.C. Dr. Biswal began his presentation by discussing the basic requirements for label claims against viruses. The requirements are chemistry, manufacturing and controls information, pharmacology/toxicology data, antiviral activity, and clinical data on safety and efficacy in human subjects. Virological considerations include the rationale for the proposed indication, non-clinical antiviral activity to assess the risk/benefit for clinical trials and the clinical virology. The non-clinical data would address the mechanism of action, antiviral activities in vitro and in vivo, drug resistance and combination therapy (synergistic, antagonistic or additive effects). To make an antiviral label claim for any drug product, the following is required. First, the claim is limited to the particular virus being evaluated. Second, both non-clinical and clinical demonstration of the efficacy and safety of the drug is required. A very limited number of topical antiseptics have been developed for and approved with antiviral claims. Denavir and Zovirax have been approved against HSV infections and Abreva was approved for the treatment of cold sores without any antiviral claim. A topical formulation of nonoxynol-9 was not approved for the prevention of HIV transmission. Topical antiseptics represent: handwashes and skin cleansers, chemical barriers applied to skin, coatings on gloves, antiseptics packaged with condoms and antiseptics for use in the vaginal tract. Three major issues exist for topical antiseptics as antivirals. Antiseptic product formulations are quite diverse (e.g., alcohols, iodines, xylenols, etc.) and show variable antiviral activity. The assay procedures for the inactivation of cell-free and cell-associated viruses in the presence and absence of body fluids or cell debris have not been adequately addressed. Finally, there is a lack of experimentally defined criteria to evaluate the optimal time of exposure of any virus to any of the topical antiseptic preparations used to achieve a safe and standardized level of reduction of virus titer in a non-clinical or clinical setting. Dr. Biswal presented data on the inactivation/reduction time of several topical antiseptics against a variety of viruses. The published findings indicated that nonenveloped viruses were equally susceptible as the enveloped viruses to the typical topical antiseptic products and that certain active ingredients in topical products may not be any better than tap water in inactivating/eliminating infectious viruses. In one scientific paper, researchers noted that routine use of antimicrobial soap and water is usually considered to be quite adequate for the decontamination of hands. The use of a less effective product may be harmful by spreading a localized contamination to both hands, thus leading to the transmission of the virus infection. In summary, Dr. Biswal noted that there is an urgent need for the availability of safe and effective topical antiseptics with antiviral claims. He concluded with the following points. Since product formulations influence the antiviral activity, specific antiviral activity along with the therapeutic index of each ingredient (active and inactive) in the product should ASTM Post-Conference Workshop October 8, 2004 Page 15 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

16 be clearly defined. In addition, the synergistic, additive, or antagonistic antiviral effect of any combination of ingredients in the product should be established. Antiviral activities against any of the viruses (both cell-free and cell-associated) should be separately established in the presence of appropriate soil generally encountered in a clinical setting. The selection of appropriate assays and models will vary with a variety of factors. If the compound is cytotoxic, the rate of virus inactivation at concentrations relevant to the proposed use should be determined. In the case of highly infectious viruses, models utilizing pig skin and/or human skin fragments, should be researched and advanced to test the antiviral activities of topical antiseptics. Criteria to evaluate the optimal time of exposure should be established and universally accepted. Finally, the antiviral efficacy and safety test results are dependent upon so many variables; as a result, human studies demonstrating safety and efficacy of topical antiviral antiseptics should continue to be required. DISCUSSION Due to time constraints, there was no discussion. ASTM Post-Conference Workshop October 8, 2004 Page 16 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

17 THE OTC DRUG MONOGRAPH PROCESS Ms. Debbie Lumpkins, Division of Over-the-Counter Drug Products, FDA, Washington, D.C. Ms. Lumpkins began her presentation by explaining the OTC drug review. It is a retrospective review of the safety and effectiveness of OTC products on the market prior to 1972 (extended to 1975), and it was initiated to evaluate all OTC drug products not approved by the FDA and those approved based only on safety prior to Then she provided the historical context, beginning with the FD&C Act in 1938, discussing the Durham-Humphrey Amendments of 1951 and Kefauver-Harris Amendments of 1962 and concluding with the Drug Efficacy Study Implementation of 1964, all of which led to the OTC Drug Review of The OTC Drug Review is based on evaluation by drug product categories rather than by individual products. It is a multistage process involving public notice and comment rulemaking and is a determination of the general recognition of the safety and effectiveness of products. The end product is a regulation in 21 CFR parts 331 to 358 defining safe and effective active ingredients, acceptable use concentrations, combinations of active ingredients, labeling and final formulation testing. Ms. Lumpkin reviewed eligibility for the OTC process. A drug is permitted for OTC sale unless it may be safely sold and used only under a prescription because of toxic or harmful effects, method of use or other collateral measures necessary for its use. Initially, products were accepted into the review regardless of the marketing history. Products included were those similarly formulated and labeled products marketed in the U.S. prior to December 1975 and those that could demonstrate a significant history of OTC use outside the U.S. Ms. Lumpkins described the Time and Extent procedures. The basic principles of the Review were discussed in detail. In terms of safety, there must a low incidence of adverse reactions or significant side effects when used according to label directions and a low potential for abuse under conditions of wide availability. Proof of safety is determined by adequate tests under conditions of use, results of significant human marketing experience, published studies and may be corroborated by unpublished data. Effectiveness is defined as a reasonable expectation that in a significant proportion of the population, the drug will provide clinically significant relief as claimed according to the label directions and warnings. Proof of effectiveness is determined by adequate and well-controlled clinical trials and generally published studies. Isolated case reports, random experience and data lacking details sufficient to permit scientific evaluation are unacceptable as evidence of effectiveness. Evaluation of the categorization will include an assessment of the benefit-to-risk ratio for the product. In terms of combinations, two or more actives may be combined, and each active must make a contribution to the claimed effect. Combining must not decrease the safety and effectiveness of any of the active ingredients. ASTM Post-Conference Workshop October 8, 2004 Page 17 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

18 Labeling of OTC products must be clear and truthful and not false or misleading. The label should include intended uses and results and adequate warnings against unsafe use or side effects. Manufacturers must use terms likely to be read and understood by ordinary individuals. There are three classifications in the Monograph. Category I contains products generally recognized as safe and effective while Category II products are not generally recognized as safe and effective. Category III is reserved for products where insufficient data are available to permit final classification. The OTC Drug Review process has several steps. There is a call for data followed by a panel report. Then the FDA prepares a proposal that will eventually become a final rule. Compliance to the rule is the final step. Each step is published in the Federal Register with opportunity for comment, submission of new data and comments on new data and information. The FDA evaluates and responds to comments and submitted data in the preamble of the regulation. Prior to the final rule, products included in the review may continue to be marketed. However, marketing is subject to the risk that the product will need to be brought into compliance with the final rule. Marketing of Time and Extent Application products only occurs with the publication of an enforcement policy or a final rule. Once the Final Rule is published, compliance is required by its effective date. Compliant products do not require preclearance to market, but non-monograph products are considered new drugs that do require preclearance for marketing. Ms. Lumpkins discussed the citizen petition and its impact on the Monograph process. The citizen s petition is a request for the FDA to take or refrain from taking an action. It is an opportunity for public comment that may be submitted at any time during or after the OTC rulemaking process. Ms. Lumpkins presented the Healthcare Antiseptic as a case study to show the impact of citizen s petitions on the rule-making process. DISCUSSION Dr. Jerry Newman: How does the TFM status relate to the antiviral citizen s petition? Ms. Lumpkins: If the petition were granted, another proposal would be initiated. Dr. David Macinga: Could you comment on combinations of actives? Are you considering combinations? Ms. Lumpkins: You must be aware of the FDA s policy on combinations. Each active cannot affect the safety or efficacy of the other. Combinations will be considered in the final rule. Dr. Syed Sattar: What is the status of the June 1994 TFM? Ms. Lumpkins: The FDA is still in the process of evaluating the huge amount of data submitted. ASTM Post-Conference Workshop October 8, 2004 Page 18 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

19 Dr. Jerry Newman: Are you still splitting the TFM into healthcare antiseptics and first aid antiseptics? Ms. Lumpkins: Splitting into two doesn t work and we will end up in the same place. We may split the rulemaking further and refer to it as consumer healthcare and food handler products. Dr. Michael Dolan: What is the timeline for the final rule? Ms. Lumpkins: Numerous layers of clearance are needed. I can t give a time. Ms. Rhonda Jones: Is the next iteration a TFM or a proposal? Ms. Lumpkins: Not sure that we can go directly to a final monograph. If the petition is granted, it will go to a proposal. Unidentified: Are you waiting for more data on dual actives? Ms. Lumpkins: No Ms. Donna Suchmann: Does the fact that Canada is accepting antiviral claims have any impact on your decision? Ms. Lumpkins: We will consider the information and determine how it works for us. We need to do what is best for us. Ms. Rhonda Jones: How does this TFM rank in priority in your office? Ms. Lumpkins: Very high priority. These are very important products and we want to move the process along. Unidentified: What was the basis for reopening the monograph last year? Ms. Lumpkins: The number of citizen s petitions and the large body of data. Dr. Betsy Anderson: How will the Agency get back to industry suppliers of active ingredients? Ms. Lumpkins: We want to give them notice and are working on the details. Unidentified: You mentioned that once the final rule is published, compliance must occur right away. Is this true? Ms. Lumpkins: The Agency gives people an adequate amount of time to comply, usually one year to fall in line with compliance. Dr. John Mitchell: The meeting that did not take place last May, was it to harmonize the CDC and FDA? ASTM Post-Conference Workshop October 8, 2004 Page 19 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

20 Ms. Lumpkins: The meeting was to revolve around testing issues. Dr. Syed Sattar: For input to be given to the FDA, does it have to be in the form of a citizen s petition? Ms. Lumpkins: No, but this is the safest and best way to submit. ASTM Post-Conference Workshop October 8, 2004 Page 20 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

21 PROCEEDINGS OF THE FIRST WORKSHOP ON ANTIVIRAL CLAIMS FOR TOPICAL ANTISEPTICS A SUMMARY Dr. Albert Sheldon, Antibiotic and Antiseptic Consultants, Inc. Dr. Sheldon provided an overview of the workshop held by the FDA in The objectives were to address various problems and prospects of developing and testing topical antiseptics for their ability to inactivate cell-free and cell-associated virus and to provide manufacturers with a strategic approach for development and marketing of effective topical antiviral antiseptics. At the time, CDER did not have standardized methods or a list of surrogates so they developed a tier-based approach to evaluate and consider for approval such products. The nonclinical strategy for antiviral drug product development included details such as mechanism of action, intended viral targets, virus concentration/inactivation kinetics, product formulation and validation of in vitro test methods and animal models. In addition, clinical trials were required to demonstrate efficacy, and the trial design (patients vs. subjects) was dependent on the labeling claim. Several issues were discussed at the workshop. In terms of methodology, standardization of methods, validation of surrogate virus and validated pass/fail criteria did not exist. The requirements for antiseptics and disinfectants were not the same. Labeling claims were examined such as virus specific versus general virucidal and the difference between consumer versus professional claims. The conclusions from the workshop were three-fold. First, the Agency will use the tier approach for antiviral drug product development of antiseptics. Second, the information gathered from the tier approach will be used to develop surrogate models. Finally, the Agency will continue to encourage further research and submission of data to help address these issues. ASTM Post-Conference Workshop October 8, 2004 Page 21 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

22 SUMMARY OF PRESENTATIONS Dr. Daryl Paulson, Bioscience Laboratories, Inc. This meeting has addressed the testing and labeling claims for antiviral products for use on the hands. Dr. Boyce addressed the fact that hand-to-hand transmission is important in viral infections and the use of alcohol products helps prevent such transmission. These products, however, need to be mild towards the hands. Dr. Sattar noted that there is low relevance for pre-op and surgical preparations but high relevance for handwashes intended for consumers, healthcare professionals, and food handlers. There also needs to be harmonization of methods. Dr. Bidawid showed that viruses can be transferred from hands to food and back again and that soap and water is just as effective as alcohol in reducing the spread of viruses. Dr. Acheson described the importance of scrubbing, rinsing and drying of hands in the prevention of food contamination. He also noted that alcohol is not always effective. Dr. Ijaz reviewed the methods for testing antiviral products and discussed the differences among using fingertips, fingerpads and the whole hand. Dr. Biswal explained the need for effective products but showed data that water may be just as effective as products containing active ingredients. Ms. Lumpkins reviewed the OTC drug process and Dr. Sheldon brought us right back to the beginning by asking what advances have been made by the Agency to address or advance the issues and thoughts presented during the 1994 workshop. ASTM Post-Conference Workshop October 8, 2004 Page 22 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

23 PANEL DISCUSSION Expert Panel: Dr. David Acheson, Dr. Shamim Ansari, Dr. Sabah Bidawid, Dr. Ward Billhimer, Dr. Nilamber Biswal, Dr. John Boyce, Dr. Peter Coderre, Ms. Debbie Lumpkins, Dr. M. Khalid Ijaz, Mr. Dan Klein, Dr. David Macinga, Dr. Jerry Newman, Dr. Julian O Rear, Dr. Syed Sattar, Dr. Lawton Seal, Dr. Albert Sheldon, Ms. Donna Suchmann, Ms. Chris Turner, and Ms. Carla Weisend Dr. Daryl Paulson: In regard to Al Sheldon s question, what advances have been made since the FDA workshop in 1994? Dr. Syed Sattar: There have been considerable advances in the last several years. In 1994, there were no acceptable standard test methods but now we have standard methods. We have considerable information on potential surrogates and have broadened the number of agents that can be tested. We have increased our knowledge base without funding from the FDA. All the work was done voluntarily in the U.S. and other parts of the world, and overseas scientists have corroborated the work conducted in the U.S. The publications presented by the speakers do not negate our arguments but support the need for effective products. Ineffective products can spread infection. The mechanism of action of these products or ingredients is not practical; this is the antibiotic mindset, where we are interested in a site of action. The antiseptics we are talking about are broad spectrum, and it is difficult to understand the mode of action. Alcohol doesn t target any specific enzyme but rather denatures protein. It is a waste of time to find the mechanism of action. Dr. Al Sheldon: How is a surrogate virus selected/identified? Ms. Donna Suchmann: Neither the FDA or EPA has accepted a surrogate for Norovirus. MICROBIOTEST has submitted a protocol with a surrogate for agency review. Dr. M. Khalid Ijaz: Surrogates are selected based on biological similarities of viruses. The Noroviruses virus protocol that was approved by the agency was based on information in the scientific literature. The feline calicivirus as surrogate for Noroviruses was developed following the basic principles adopted by the EPA for using the surrogates in virucidal testing during acceptance of HBV and HCV protocols. Dr. Julian O Rear: Mechanism of action is important in the study of resistance. The FDA does not provide funding for this type of work. Since 1994, there is the pre-ind process, which is now more sophisticated. The process is open to everyone and can help you decide where to spend your resources. The FDA team leaders will provide feedback (comments off the record), and this can be done more than one time. Some viruses not discussed at this meeting are bioterrorism agents. How do you study a virus not available in the clinical setting, for example, smallpox? ASTM Post-Conference Workshop October 8, 2004 Page 23 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

24 Dr. Daryl Paulson: As far as topical antiseptics are concerned, what has been done for Rotavirus and Adenovirus? Is Dr. Sattar s method adequate? Dr. Julian O Rear: It is difficult to relate log reductions to clinical benefits, and the benefit will vary from virus to virus. This issue needs to be addressed. Vaccinia and smallpox viruses grow to trillions and a ten-fold decrease in the organism will provide no benefit. Dr. Daryl Paulson: There is conflicting evidence on the efficacy of alcohol. What is the projected efficacy of alcohol? Ms. Donna Suchmann: What alcohols are we talking about? Dr. Syed Sattar: In the published literature, the alcohols tested differed in level and type. Some formulations also have other ingredients that provide an additive benefit. Ethanol at 60%-70% on skin is less effective against non-enveloped viruses than enveloped. There are also differences among non-enveloped viruses; Rotavirus is more susceptible than Calicivirus. When choosing a surrogate, these factors need to be considered. You want a surrogate that is reasonably resistant. We now have methods than can distinguish these viruses, so better surrogates can be chosen. The choice depends on safety. The EPA statement that every virus on the label claim needs to be tested is risky, costly and not as safe. The ease with which you can handle the virus in the lab needs to be considered. Ideally, you would like to test Hepatitis B but it is difficult to work with in the laboratory. When choosing an antibiotic or antimicrobial therapeutic agent, there needs to be a balance between toxicity and therapeutic effects. For a topical handwash, you can afford to use more of the agent than necessary because toxicity is not as bad as when you inject the agent. As a result, resistance is less of an issue. Dr. Nilamber Biswal: Will alcohol eliminate/reduce the virus titer? It depends on the type of alcohol. In previously reported studies, the conditions are variable, and the results are dependent on how you do the test, who performs the test, the cell lines used, and the type of alcohol tested. Not all alcohols work to the same extent. A topical antiseptic is not just one ingredient. If several ingredients were combined, one would hope to see a better product when other materials are added, for example, surfactants. You need to know what effect each ingredient has on the virus. Several methods exist to test the products. The whole hand method is not as good as the fingerpad procedure, but industry could choose to use it. This is a difficult situation from a regulatory point of view. In 1994, a 3-5 log reduction was good. Now a 1-2 log reduction is considered good. Who decided what the reduction should be and what is the clinical evidence for this decision? The desired reduction needs to be proven in non-clinical and clinical settings. Unidentified: The regulatory agencies want to see efficacy against each virus. We could end up with 45 different products with activity against single viruses and then which one would a doctor choose? We need a broad antiviral indication supported by good models using surrogates. ASTM Post-Conference Workshop October 8, 2004 Page 24 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

25 Dr. Daryl Paulson: We need this type of testing. What guidelines are needed? Dr. George Fishler: A drug is only approved based on its label claims and intended action. Is a method demonstrating a reduction enough to make a claim? Here are four hypothetical claims: reduces rotavirus on hands; reduces the transmission of rotavirus, which caused diarrhea; reduces the incidence of diarrhea due to rotavirus; and reduces the incidence of foodborne illness due to rotavirus. Are they the same or different claims? Do they need different testing? If you show a reduction of rotavirus, is this the claim or does it imply more? What is the level of proof needed? Dr. Dick Norton: We need to focus on the word reduction. When penicillin was discovered, not much was known about the drug but it did save many lives. Later, the mechanism of action was discovered. These products need to be marketed now. The current methods should be used to market these products and make reasonable claims. Dr. Syed Sattar: How does a physician choose a product when they claim activity against different viruses? In a field situation, you don t know what the target is. If an antiviral product is used to treat a cold sore, you know what the target is. For healthcare workers, the target is unknown. Models are needed to make broad claims. In regards to Dr. Biswal s comment about the different test methods, Dr. Ijaz did not say that the methods are mutually exclusive. Both methods could be used to reinforce the claim. The fingerpad method is more rigorous, versatile and easier to use. You could start with this method and then use the whole hand procedure. Dr. Jerry Newman: When looking for new drugs, the monograph process is used. How can we move forward? For the citizen s petition, is the question primarily scientific or legal? Ms. Debbie Lumpkins: The citizen s petition raises a lot of questions. There is little experience with these types of claims and products. The science needs to be worked out and we still have a way to go. Dr. M. Khalid Ijaz: The different methods discussed in this symposium have been widely published in peer-reviewed journals. In addition, these methods have been approved by Standard setting organizations like ASTM. These methods have been discussed and published in the literature. What methods would the FDA like us to use? Dr. Nilamber Biswal: Are you inactivating during replication? Comments on the antiviral activity are needed, and the information should come from more than just one method. As a scientist you know what you want to test. Some products have activity against viruses and others do not. The issue arises when a product is approved and then a publication shows data that the product is ineffective. From a regulatory point of view, we need to take into account what is in the literature. Dr. M. Khalid Ijaz: What performance criteria FDA would like to see for virus elimination by the hand hygiene products using these methods? Dr. Nilamber Biswal: The fingerpad region is different than other parts of the skin. ASTM Post-Conference Workshop October 8, 2004 Page 25 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

26 Dr. M. Khalid Ijaz: As Dr. Sattar mentioned one could do initial evaluation by fingerpad method and perform confirmatory test using the whole hand method. Would that be acceptable to FDA? Dr. David Macinga: The antiviral citizen s petition makes the process of the antibacterial TFM more complex and extends the timeline. Will the monograph contain antiviral claims? Does it make sense to exclude antiviral claims so that the monograph can be issued? Would the creation of an antiviral TFM allow products to be marketed and the agencies to obtain the data? Ms. Debbie Lumpkins: The FTC drug review has a defined scope. It is difficult to see how a proposed rule for antiviral claims would allow much in terms of marketing. Dr. Betsy Anderson: I heard that there was draft proposed rulemaking for antiviral products. Ms. Debbie Lumpkins: I have no knowledge that it was made or that a draft exists. Unidentified: I am not aware of this draft document. It would be somewhat outdated now. Unidentified: We give examples of treatment and prevention and this requires clinical data. We have less experience in the handwashing area. How can we have multiple products with multiple claims? It is envisioned that a product with a single claim would still be useful. We don t want to migrate from established principles. Nonoxynol-9 was pursued but now it has been shown to enhance the transmission of HIV. HIV RNA is a suitable surrogate for the clinical endpoint; however, it required a considerable amount of data to get to this point. Dermatitis can help increase disease and we need clinical data to show this. Dr. Greg Art: Claims need to be identified that are financially attractive to manufacturers. We need to focus on claims that make sense. Dr. M. Khalid Ijaz: In conclusion, we need to continue this dialog. We greatly appreciate the FDA responding to us and being a part of this symposium. It has been agreed that the ASTM E35.15 antiviral task force will continue working with you. The questions raised by the FDA speakers will be documented. I have been very pleased with the symposium and want to thank the speakers, ASTM, the conveners, the organizing committee, the co-chairs of E35.15, Dan Smith, Donna Suchmann and the audience for participating. ASTM Post-Conference Workshop October 8, 2004 Page 26 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

27 SPEAKER BIOGRAPHIES Dr. David William Kennedy Acheson, M.D., F.R.C.P. Director of Food Safety and Security Staff and Chief Medical Officer Center for Food Safety and Applied Nutrition, FDA Dr. Acheson graduated from medical school in 1980 from the University of London, and following training in internal medicine and infectious diseases in the United Kingdom moved to New England Medical Center and Tufts University in Boston in As an Associate Professor at Tufts University he undertook basic molecular pathogenesis research on foodborne pathogens, especially Shiga toxin-producing E. coli, from 1987 until In 2001 Dr Acheson moved his laboratory to the University of Maryland Medical School in Baltimore to continue research on foodborne pathogens. In September 2002 he took up a position as Chief Medical Officer at the Food and Drug Administrations Center for Food Safety and Applied Nutrition and in January 2004 also became the Director of Food Safety and Security in the Center for Food Safety and Applied Nutrition. Dr. Acheson is internationally recognized both for his public health expertise in food safety and his research in infectious diseases, and is a fellow of both the Royal College of Physicians (London) and the Infectious Disease Society of America. Dr. Sabah Bidawid, PhD Manager of Research, Health Canada, Ottawa, Ontario, Canada Dr. Sabah Bidawid obtained his PhD degree from the University of Ottawa, Canada, in Microbiology and Immunology. In 1990, Dr. Bidawid joined Health Canada s Food Directorate as a researcher on foodborne viruses, developing rapid virus detection methods and conducting studies on virus transfer, survival and inactivation in foods. Additionally, Dr. Bidawid is the Chief of the Microbiology Research Division and the current President of the Food and Environmental Virology Network. Dr. Nilambar Biswal, Ph.D. Microbiologist, Division of Anti-Viral Drug Products, FDA, Washington, D.C. Dr. Biswal graduated as a Ph.D. in Microbiology and Public Health from Michigan State University, East Lansing, Michigan. After a two-year stint as a Research Virologist at the Virus Laboratory, University of California, Berkeley, CA, he joined the graduate faculty at the Baylor College of Medicine, Houston, Texas. After ten years of teaching and research on RNA tumor viruses and herpes viruses at Baylor, Dr. Biswal joined the graduate faculty at the School of Medicine, University of Maryland at Baltimore. He served as the Head, Division of Molecular Biology, University of Maryland Cancer Center, Baltimore, before joining the Division of Antiviral Drug Products, FDA, in 1988 as a Regulatory Review Scientist-Microbiologist. In addition to the review workload as an expert virologist with specialty on herpes viruses, Dr. Biswal taught courses at the Staff College (of Center for Drug Evaluation and Research) on Biotechnology and ASTM Post-Conference Workshop October 8, 2004 Page 27 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

28 Regulatory Sciences to FDA review scientists and medical officers. Realizing the need for the development and approval of topical antiseptics with antiviral claims, he organized the First Workshop on Antiviral Claims for Topical Antiseptics in He is glad to participate in this ASTM Post-Conference Symposium on a very similar topic. Dr. John M. Boyce, MD Clinical Professor and Chief of the Section of Infectious Diseases, and Hospital Epidemiologist, Hospital of Saint Raphael, Yale University, New Haven, CT. Dr. Boyce is a recognized expert in the epidemiology and prevention of nosocomial infections caused by resistant pathogens such as methicillinresistant Staphylococcus aureus and vancomycin-resistant enterococci, and was the lead author on the new Hand Hygiene Guideline for Healthcare Settings, which was published by CDC in Dr. M. Khalid Ijaz, DVM, PhD Vice President and Director MICROBIOTEST, INC., Division of Aerobiology, Protozoology and Virology and Affiliate Professor George Mason University, Department of Molecular and Microbiology, 105B Carpenter Drive, Sterling, VA 20164, USA Phone:(703) Fax:(703) ijaz@microbiotest.com Dr. Ijaz graduated from Veterinary School and received MSc (Honors) in Microbiology from the University of Agriculture, Pakistan. He completed his PhD in Microbiology and Immunology in 1985 from the University of Ottawa Medical School. His doctoral work involved looking into aerobiological aspects of enteric and respiratory viruses. He did his post-doctoral work at the Vaccines and Infectious Disease Organization (VIDO) based on the campus of University of Saskatchewan, Canada and received an MRC Fellowship award from the Medical Research Council of Canada for carrying out work on different aspects of rota- and coronavirus vaccines. In addition to teaching in different international medical, pharmacy and veterinary schools, he has performed extensive research and published on various aspects of mammalian and avian viruses. Ms. Debbie Lumpkins Division of Over-the-Counter Drug Products, FDA, Washington, D.C. Ms. Lumpkins earned a Bachelor s degree in microbiology from the University of Maryland in 1975 and began her career with FDA as a bench analyst for the National Center for Antibiotic Analysis in She has worked in the field of molecular genetics at the National Institutes of Health and the National Institute of Alcohol Abuse and Alcoholism. She has been a member of the Division of Over-the-Counter Drug Products since 1984 and has been responsible for the development of many OTC drug monographs, one of the more notable being the proposed rule for OTC healthcare ASTM Post-Conference Workshop October 8, 2004 Page 28 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

29 antiseptic drug products. Ms. Lumpkins is currently the Team Leader for the development of the final rule for OTC healthcare antiseptics. Dr. Syed A. Sattar, Ph.D. Director, Centre for Research on Environmental Microbiology (CREM) Faculty of Medicine, University of Ottawa 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5 Phone: (613) X 8314 or 8568 Fax: (613) ssattar@uottawa.ca Dr. Sattar is Director of the Centre for Research on Environmental Microbiology (CREM), Faculty of Medicine, University of Ottawa. For the past 34 years, he has been conducting research on the fate of human pathogens in water, air, food, soil as well as on medical devices, environmental surfaces and human hands. A major part of his research has been on the use of microbicides in environmental control of infectious agents. He has authored two books, several monographs and lab manuals, and published more than 130 research papers, numerous book chapters and technical reports. He has also given over 140 presentations at scientific meetings and has delivered more than 200 invited lectures worldwide. He is an advisor to Health Canada and the U.S. Environmental Protection Agency and an active member of several international standards-setting organizations including ASTM International. Many methods he has developed for the evaluation of microbicides are now international standards. He is a member of the editorial boards of the American Journal of Infection Control as well as Infection Control and Hospital Epidemiology. Dr. Albert T. Sheldon, Jr. PhD Antibiotic and Antiseptic Consultants, Inc. Silver Spring, MD Albert T. Sheldon is president of Antibiotic and Antiseptic Consultants, Inc. He worked for the Food and Drug Administration for 32 years in the Center for Drug Evaluation and Research, Division of Anti-infective Drug Products as a microbiology review officer, Microbiology Team Leader and Supervisor where he was the principle advisor to Division Director with responsibility for planning, coordinating, and evaluating program activities for the discipline of Microbiology. Dr. Sheldon lead and served on Division, Office, Center, and Agency Task Forces charged with developing policy, guidance, and problem solving of scientific and regulatory issues. He functioned as agency scientific expert on issues regarding antibiotic resistance; chaired or served on numerous committees charged with addressing targeted drug development for drug resistant organisms of public health concern. He was instrumental in developing the requirements for the assessment of antiseptic drug products and functioned a liaison between the FDA and the American Society for Testing and Materials (ASTM) and the National Committee for Clinical Laboratory Standards (NCCLS). Dr. Sheldon graduated from the Columbian School of Arts and Sciences, George Washington University with a PhD in genetics. His undergraduate and master degrees in Microbiology were obtained from the New Mexico Highlands University. ASTM Post-Conference Workshop October 8, 2004 Page 29 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

30 ASTM Post-Conference Workshop OVER-THE-COUNTER TOPICALS: ASSESSING THE NEED FOR TESTING AND LABEL CLAIMS AGAINST VIRUSES October 08, 2004 LIST OF PARTICIPANTS Acheson, David, MD Center for Food Safety and Applied Nutrition, US Food and Drug Administration College Park, MD Anderson, Betsy The Cosmetic, Toiletry Association Washington, DC Ansari, Shamim, PhD Colgate Palmolive Piscataway, NJ Art, Greg Aplicare Inc. Branford, CT Bashir, M. Hamid, MD MICROBIOTEST, Inc. Sterling, VA Baxter, Kathleen Hill Top Research Inc. Cincinnati, OH Bennett, Mary Ecolab, Inc. St. Paul, MN Bidawid, Sabah, PhD ASTM Post-Conference Workshop October 8, 2004 Page 30 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

31 Health Canada Ottawa, Ontario Billhimer, Ward, PhD Procter & Gamble Cincinnati, OH Birnkrant, Debra Center on Drug Evaluation and Research, US Food and Drug Administration Rockville, MD Boyce, John M, MD Hospital of Saint Raphael New Haven, CT Brady, Ann Hill Top Research Inc. Cincinnati, OH Bruch, Mary K. MicroReg Inc. Hamilton, VA Chiang, Mike, PhD Lonza Allendale, NJ Coderre, Peter, PhD US Food and Drug Administration Rockville, MD Cords, Bruce Ecolab, Inc. St. Paul, MN Czechowski, Melvin, PhD Church & Dwight Princeton, NJ Dolan, Michael GOJO Industries Akron, OH Donna Suchmann MICROBIOTEST, Inc. Sterling, VA ASTM Post-Conference Workshop October 8, 2004 Page 31 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

32 Ebers, Mike Steris Corporation St. Louis, MO Fanselle, Wendy Center for Food Safety and Applied Nutrition US Food and Drug Administration College Park, MD Fischler, George Dial Corp. Scottsdale, AZ Frazier, Tia US Food and Drug Administration Rockville, MD Fuls, Janice Dial Corp. Scottsdale, AZ Ganley, Charles US Food and Drug Administration Rockville, MD Glenn, Steve GMP Companies Ft. Lauderdale, FL Hepp, Mark, PhD Center for Food Safety and Applied Nutrition US Food and Drug Administration College Park, MD Hollingsworth, Angela MICROBIOTEST, Inc. Sterling, VA Ijaz, M. Khalid, DVM, PhD MICROBIOTEST, Inc. Sterling, VA Jackson, Michelle M. US Food and Drug Administration Rockville, MD Jones, Karen Colgate Palmolive Piscataway, NJ ASTM Post-Conference Workshop October 8, 2004 Page 32 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

33 Jones, Rhonda Scientific & Regulatory Consultants, Inc. Columbia City, IN Kane-Rogers, Colleen US Food and Drug Administration Washington, DC Ketkoski, Roberta Unilever Trumbull, CT Klein, Dan Steris Corporation St. Louis, MO Kruszewski, Francis, PhD The Soap and Detergent Association Washington, DC Lumpkins, Debbie US Food and Drug Administration Rockville, MD Macinga, David, PhD GOJO Industries Akron, OH Mahon, Connie US Food and Drug Administration Rockville, MD Manzo, Christine Reckitt Benckiser Inc. Montvale, NJ McNamara, Barry, PhD Procter & Gamble Cincinnati, OH Mitchell, John A., PhD BioScience Laboratories Bozeman, MT Newman, Jerry, PhD STERIS Corporation St. Louis, MO ASTM Post-Conference Workshop October 8, 2004 Page 33 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

34 Norton, Richard, MD DN Consultants Rockville, MD O Rear, Jules, PhD Antiviral Drugs US Food and Drug Administration Rockville, MD Osborne, Steve US Food and Drug Administration Washington, DC Paulson, Daryl, PhD BioScience Laboratories Bozeman, MT Paulson, Marsha BioScience Laboratories Bozeman, MT Pelov, Victor P. Johnson & Johnson Skillman, NJ Resch, Carol Unilever Edgewater, NJ Richards, Stephen Consumer Product Testing Company Fairfield, NJ Rosebraugh, Curtis US Food and Drug Administration Rockville, MD Sattar, Syed A., PhD University of Ottawa Ottawa, Ontario Canada Schulz, Rhonda Ecolab, Inc. St. Paul, MN Scoart, Sally Ecolab, Inc. St. Paul, MN ASTM Post-Conference Workshop October 8, 2004 Page 34 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

35 Seal, Lawton, PhD Healthpoint St. Antonio, TX Sheldon, Albert T., PhD Antibiotic & Antiseptic Consultants Silver Spring, MD Smith, Kyle T. Reckitt Benckiser Inc. Montvale, NJ Stahl, Julie 3M St. Paul, MN Starobin, Anna Kay Chemical Co. Swal, N.B. US Food and Drug Administration Rockville, MD Vincent, Carol Unilever Trumbull, CT Walter, Richard, PhD Dow Chemical Midland, MI Weisend, Carla BioScience Laboratories Bozeman, MT Wesenberg-Ward, Karen, PhD BioScience Laboratories Bozeman, MT White, Curtis Aegis Environments Midland, MI Woods, Bill Lonza Allendale, NJ ASTM Post-Conference Workshop October 8, 2004 Page 35 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

36 Young, Jeff Dow Chemical Midland, MI Zhou, Xin US Food and Drug Administration Washington, DC ASTM Post-Conference Workshop October 8, 2004 Page 36 Over-the-Counter Topicals: Assessing the Need for Testing and Label Claims against Viruses

37 Over-the-Counter Topical Antimicrobials in Contact with Food Food and Drug Administration Center for Food Safety and Applied Nutrition David Acheson, MD, Chief Medical Officer Mark Hepp, Consumer Safety Officer Capt. Wendy Fanaselle, MS, RS, Consumer Safety Officer ASTM Post-Conference Symposium October 8, 2004

38 Center for Veterinary Medicine FDA Headquarters Office of the Commissioner Office of General Counsel Center for Food Safety and Applied Nutrition Center for Biologics Evaluation and Research Center for Drug Evaluation and Research ASTM Post-Conference Symposium October 8, 2004 Center for Devices and Radiological Health

39 Presentation Overview The FDA Food Code: David Acheson Foodborne Pathogens Transmitted by Hands: David Acheson Controlling Hand Transmission of Foodborne Pathogens: Wendy Fanaselle Approval Process in CFSAN: Mark Hepp ASTM Post-Conference Symposium October 8, 2004

40 Food Code represents FDA s best advice for Uniform system of regulation; Safe food service through researched and recommended practices; Food is protected, unadulterated, and honestly presented. ASTM Post-Conference Symposium October 8, 2004

41 Intent of the Food Code Designed to minimize foodborne illness by focusing on the leading FBI risk factors Promotes Uniformity 75 State & Territorial local regulatory food agencies Provides jurisdictions with a scientifically sound technical and legal basis for regulating the retail food industry. ASTM Post-Conference Symposium October 8, 2004

42 ASTM Post-Conference Symposium October 8, 2004 Food Code 5 Key Interventions 1. Demonstration of Knowledge 2. Employee Health 3. Time / Temperature 4. Hands a Vehicle of Contamination 5. Consumer Advisory

43 Food Code 5 Key FBI Risk Factors 1. Poor Personal Hygiene 2. Improper Holding Temperatures 3. Inadequate Cooking 4. Contaminated Equipment 5. Food from Unsafe Sources ASTM Post-Conference Symposium October 8, 2004

44 Food Code Interventions to Control the Contamination of R-T-E foods by Food Workers Are: Exclusion & Restriction of ill workers Handwashing as specified in the Food Code No bare hand contact with R-T-E foods unless otherwise approved ASTM Post-Conference Symposium October 8, 2004

45 Pathogens Often Transmitted by Food Contaminated by Infected Persons: CDC List I: I: Federal Register, Vol. 69, No.191. Oct. 4, 2004 Norovirus Hepatitis A virus Salmonella Typhi Shigella species Staphylococcus aureus Streptococcus pyogenes ASTM Post-Conference Symposium October 8, 2004

46 Norovirus Virus Bar = 50 nanometers Reported as the single most common cause of gastroenteritis in the western world--cdc leading cause of foodborne illness in the USA (66.6% of all foodborne illness or 9,200,000 cases/yr) ASTM Post-Conference Symposium October 8, 2004

47 ASTM Post-Conference Symposium October 8, 2004 Norovirus Norwalk virus Winter Vomiting Disease Calicivirus-- NAKED SINGLE STRAND RNA No Envelope ----Hydrophilic hour incubation period Illness duration of hours Usually a mild illness ---very short strain specific immunity Vomiting, diarrhea, etc. Outbreaks documented resulting from pre and post symptomatic individuals

48 Norovirus Challenges Highly Infectious: transmitted via fecal oral route and inhalation of microscopic droplets from vomitus High secondary attack rate: >50%. Infectious Dose: ~ viral particles Shed in Feces: ~ 10 7 viral particles/ gram of feces Projectile vomiting associated with NoV infection: ~3 X 10 7 virus particles as an aerosol ASTM Post-Conference Symposium October 8, 2004

49 Controlling Foodborne Illness Pathogen Transmission on Hands ASTM Post-Conference Symposium October 8, 2004

50 Problems in Controlling Norovirus Can not culture: only source is from sick individuals No universally accepted surrogate FeCV-F9 has been widely studied, but is a respiratory virus strain E. Dusizer, et.al., 2004, Compared FeCV- F9 to CaCV no.48 strain & Norovirus (genogroup II.4): Virus inactivation was temp. & time dependent & similar ASTM Post-Conference Symposium October 8, 2004

51 Norovirus Challenges Need Universally recognized surrogate Need to determine clinically relevant reduction level: reduction in infectivity found before elimination of NoV RNA through PCR detection ASTM Post-Conference Symposium October 8, 2004

52 Hand Contamination in Food Service Improper or lack of handwashing is a problem in retail and food service Hands play 2 different roles in foodborne illness caused by contamination of food Source of contamination Vehicle of contamination ASTM Post-Conference Symposium October 8, 2004

53 Hand contamination De Witt, et al Examined the fecal contamination level of the hands, after handwashing (E.coli as an indicator). Found E.coli in 25% of sampled individuals after stools (ave. log 2.3 CFU E.coli per sample) after handwashing ASTM Post-Conference Symposium October 8, 2004

54 Hand Contamination De Wit s studies Continued Handwashing decreased the E.coli counts on the hands, but did not eliminate it. Concluded that infected individuals shedding at high levels will have high hand contamination levels, even with hygiene practiced. ASTM Post-Conference Symposium October 8, 2004

55 HANDWASHING PROCEDURE 2001 FOOD CODE: Every Stage of Handwashing is Important 1. Scrub using vigorous friction, with cleaning compound on hand & arm surfaces, fingers, finger tips, and areas between the fingers for at least seconds. 2. Rinsing hands under strong velocity & volume of clean, running water 3. Drying hands thoroughly using either a heated air, hand dryer, individual disposable towels or a continuous clean towel system ASTM Post-Conference Symposium October 8, 2004

56 Handwashing Elements Friction is the most important element in removing transients ASTM Post-Conference Symposium October 8, 2004

57 Handwashing Continued: Handwash Time: Second Scrub Soap: surfactant effect in removing grease, soil, and debris from the hands. Water Temp: Soap efficacy is tested at ASTM Std s = 40 C +/- 2 degrees ~ (100 F F) Food Code: minimum water temp: 100 F ASTM Post-Conference Symposium October 8, 2004

58 Scientific Literature Tells Us: Proper handwashing: Transient bacteria: 2-3 log reduction Transient viruses & protozoa: 2 log reduction ASTM Post-Conference Symposium October 8, 2004

59 No Bare Hand Contact of RTE Food Limitations ASTM Post-Conference Symposium October 8, 2004 Utensils (such as gloves) Education on proper use Choosing proper utensil Glove integrity Procedures difficult without use of bare hands Alternatives for latex allergies

60 ASTM Post-Conference Symposium October 8, 2004 Gloves Leak! 13% of Gloves Have Failure However, no correlation found between the the leakage & microbial transfer Olsen (1993): 77% of the time, gloves with leaks still prevented hand contamination Montville (2001): bacterial transfer through food service gloves: 0.01% transfer rate with gloves----10% transfer rate without gloves on washed hands

61 Hand Antiseptics/Sanitizers : Allowed after handwashing but not always effective in food service Can alcohol-based hand gels serve as a suitable alternative to handwashing for retail and food service workers? NO Types of pathogens are different Efficacy & approval of alcohol-based hand gels Soil on the hands ASTM Post-Conference Symposium October 8, 2004

62 Limitations of Alcohol-Based Hand Antiseptics/Sanitizers in Food Service Impacted by soil Neutralized by protein Impacted by moisture Limited effect on protozoan oocysts and foodborne viruses E. Duizer, et.al., 2004, found incomplete inactivation of NoV with 70% ethanol ASTM Post-Conference Symposium October 8, 2004

63 Hand Antiseptics/Sanitizers Considered a DRUG by FDA FDA Approval Monograph New Drug Approval or + Indirect Food Additive 1. Prior Sanctioned 2. Listed Chemical ASTM Post-Conference Symposium October 8, 2004 Brand name listing: Orange Book 1. GRAS 2. Exempt under 21 CFR Meets 21 CFR 178 Indirect Food Additive

64 CFSAN Approval of Over-the- Counter Topical Antimicrobials in Contact with Food ASTM Post-Conference Symposium October 8, 2004

65 Topical Antimicrobials/ Hand Sanitizers for Food Workers Food Additive Definition: FFDCA Sec. 201(s) Center for Food Safety and Applied Nutrition Drug Definition: FFDCA Sec. 201 (g) Center for Drug Evaluation and Research ASTM Post-Conference Symposium October 8, 2004

66 Food Additive Definition Any substance, that reasonably expected to become a component of food as a result of its intended use, if such use is not Generally Recognized As Safe Except that such term does not include-- a pesticide chemical, or a pesticide chemical residue color additive substances approved for use in food prior to 1958 a new animal drug a dietary supplement ASTM Post-Conference Symposium October 8, 2004

67 Safe Food Additives Use Conforms with: a food additive regulation an effective food contact substance notification a threshold of regulation exemption issued under 21 CFR ASTM Post-Conference Symposium October 8, 2004

68 Section 409 Safety Review Evaluation of Probable consumption of the food additive Cumulative effects of such additives in the diet Safety factors recognized as appropriate for the use of animal experimentation data ASTM Post-Conference Symposium October 8, 2004

69 When a Tolerance Must be Set Clearly specify the intended technical effect Show that the use of the additive achieves the intended effect Show the minimum amount required to accomplish the intended technical effect ASTM Post-Conference Symposium October 8, 2004

70 Technical Effect of Topicals No intended effect in or on food Control microbes on humans CDER has explicit authority for such effects CFSAN advises a consultation with FDA for topical antimicrobial active ingredients ASTM Post-Conference Symposium October 8, 2004

71 Mark Hepp Food and Drug Administration Center for Food Safety and Applied Nutrition Division of Food Contact Notifications, HFS Paint Branch Parkway College Park, MD ASTM Post-Conference Symposium October 8, 2004

72 Survival, Transfer and Inactivation of Food borne Viruses: Summary of Recent Research in Canada Sabah Bidawid, Ph.D. Chief, Microbiology Research Division, BMH Health Products and Food Branch Food Directorate Health Canada ASTM Symposium, Washington, DC October 08, 2004

73 Outline Foodborne viruses Food contamination Foodhandlers and virus spread Intervention and control Conclusion Bidawid/ ASTM Washington/ Oct 2004 Health Canada

74 Organization (HC) Organization (HC) Health Products and Food Branch Food Directorate Bureau of Microbial Hazards Evaluation Division Research Division Risk Assessment Policy Novel Foods Foodborne Bacterial Pathogens Foodborne Viruses & Parasites Research Reference Services Risk Assessment Industry Submissions POLICY REGULATIONS Food Safety Advice Education Standards Guidelines

75 Viruses!!! Viruses!!! Very tiny need EM Do not multiply in foods Few particles (10-100) infection Present everywhere No antibiotics Significant impact Health / Economy Emerging viruses (SARS/ Avian Flu.) Bioterrorism..!!!!!!!!!! Bidawid/ ASTM Washington/ Oct 2004 Health Canada

76 Virus Stability & Survival Virus Stability & Survival? Stable: -20 C/yrs; RT/42% humidity/1 month? Resistant: ----> ph 3 / 3h / 25 C ----> gastric enzymes? Resistant: ----> heat 60 C/1h, chlorine? Sensitive: ----> heat: 85 C/1.5 min (shellfish), UV, High Pressure Bidawid/ ASTM Washington/ Oct 2004 Health Canada

77 Foodborne Viruses Bidawid/ ASTM Washington/ Oct 2004 Health Canada

78 Viral Food & Water Contaminants Viral Food & Water Contaminants Norwalk-&-Like viruses (NLV) Hepatitis A Virus (HAV) Rotaviruses Poliovirus Astroviruses Coronaviruses Hepatitis E virus Enteric Adenoviruses % Foodborne Disease Illnesses Hospitalizations Deaths Bacterial Parasitic Viral 7.1 Mead et al, 1999 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

79 Foodborne Illness -US 38.6 million total foodborne illnesses annually 30.9 million (80%) due to viruses (Mead et al., 1999) Caliciviruses (NLV) Hepatitis A virus Bacteria Parasites 34% 13% 50% 3% ^ 47% Bidawid/ ASTM Washington/ Oct 2004 Health Canada

80 Listeria E. coli Campylobacter Vibrios Noroviruses Hepatitis A virus Cryptosporidium Shigella Salmonella Bidawid/ ASTM Washington/ Oct 2004 Health Canada

81 Transmission Fecal-oral Person-to-Person Food & Foodhandlers Airborne (NLV) Fomites Shellfish (clams, oysters, cockles, mussels) Fruits & vegetables Ready-to-eat foods Bidawid/ ASTM Washington/ Oct 2004 Health Canada

82 Foodborne Outbreak Settings Foodborne Outbreak Settings? Restaurants? Celebratory Functions? Home (Family)? Nurseries & paediatric wards? Daycare centres and schools? Senior homes? Contained communities? Cruise ships & others? Oysters, clams, mussels.? Salads? Sandwiches? Cake & bakery products? Frosting? Strawberries? Raspberries? Water? Ice Bidawid/ ASTM Washington/ Oct 2004 Health Canada

83 NLV-Settings & Routes of Transmission 348 outbreaks (Jan. 96-Nov.2000) No data 28% Foodborne 39% Unknown 18% Waterborne 3% Person -toperson 12% CDC Bidawid/ ASTM Washington/ Oct 2004 Health Canada

84 Factors in Foodborne Outbreaks Factors in Foodborne Outbreaks > Food contamination at origin > Cross-contamination by foodhandlers (8-17%) > Lack of proper hygiene facilities > Improper cooking, hot holding, storage > Intra- and interfamilial spread Bidawid/ ASTM Washington/ Oct 2004 Health Canada

85 Survival of enteric viruses Survival of enteric viruses??? Bidawid/ ASTM Washington/ Oct 2004 Re: Koopmans & Duizer, 2004 Health Canada

86 Survival of Select Pathogens on Hands of Volunteers After One Hour % Pathogen Survival (Modified & Updated from Sattar et al.,. 1996) TEN µl OF THE TEST ORGANISM IN A SOIL LOAD WAS PLACED ON THE FINGERPADS OF ADULT SUBJECTS. THE INOCULUM WAS ELUTED AFTER 1 HOUR & THE ELUATES TITRATED FOR VIABLE ORGANISMS. 0 Canine Hepatitis Parvo A Rota S. aureus Rhino Feline Calici Adeno E. coli Paraflu 3 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

87 FCV / HAV Bidawid et al

88 HAV Survival on Lettuce at 4 C & RT HAV Survival on Lettuce at 4 C & RT VIRUS TITRE log PETRI DISH PLASTIC BAG VIRUS IN PBS DAYS 4 C 7 22 C VIRUS TITRE log PETRI DISH PLASTIC BAG VIRUS IN PBS DAYS Bidawid et al, 2000 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

89 Survival of Feline Calicivirus On Foods & Surfaces at 4 C & 22 4 C 22 C Recovery of fecal suspension-fcv from food and metal disks stored at 4 C from day 1 to day Recovery of fecal suspension-fcv from food and metal disks stored at room temperature from day 1 to day log viral count Ham Lettuce Berries Metal disks Days Log viral count Ham Lettuce Berries Metal disk Days Bidawid et al, 2004 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

90 Foodhandlers - Poor Personal Hygiene Foodhandlers - Poor Personal Hygiene Bidawid/ ASTM Washington/ Oct 2004 Health Canada

91 Virus Cross-contamination Virus Cross-contamination Transfer of Hepatitis A Virus & Feline Calicivirus (Surrogate for Norovirus) Between Human Hands, Foods & Surfaces Bidawid/ ASTM Washington/ Oct 2004 Health Canada

92 Virus Transfer: Fingerpads to Foods / Surfaces 46% HAM 13% STEEL DISK 10 µl FCV/HAV 18% LETTUCE Bidawid et al, 2000, 2004 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

93 Virus Transfer: Foods & Surfaces to Fingerpads HAM STEEL DISK 6% 10 µl FCV/HAV 7% 14% LETTUCE Bidawid et al, 2000, 2004 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

94 Transfer Interruption Transfer Interruption Water HAM Water & Soap STEEL DISK = 3.4 % (P < 0.05) 10 µl FCV/HAV Alcohol 75% liquid 62% gel LETTUCE Bidawid et al, 2000, 2004 Bidawid/ ASTM Washington/ Oct 2004 Health Canada

95 Feline Calicivirus Inactivation Surface Reagent Exposure Time Log Titre Reduction Fingerpad 65% & 75% Alc. 20 sec < 2 log Disk 65% & 75% Alc. 5 min # 5 log Disk 65% & 75% Alc. 10 min Undetectable (Sattaret al) Bidawid/ ASTM Washington/ Oct 2004 Health Canada

96 Concluding Remarks Concluding Remarks? FCV is less resistant to surface disinfectants than Hepatitis A virus.? 60% HAV & 30% FCV remain viable on the hands of adults after 1 hour.? 4 C FCV can survive for a week on metal disks & >10 days in foods.? RT FCV can survive on metal disks for several hours (up to 5 days), and for = 8 days in foods.? At 50% relative humidity and 24 C, FCV can survive in air for at least 2h.? Virus transfer between hands & foods readily occurs.? Water alone, water+soap, 75% ethanol or a 62% ethanol-based gel could reduce virus transfer from hands to foods significantly (>95%).? Bleach at >1000 ppm needed for a >99.99 inactivation in 1 min at 23 C.? Other hard surface disinfectants tested could reduce FCV infectivity by >99.9% in 1-30 minutes at 23 c. Bidawid/ ASTM Washington/ Oct 2004 Health Canada

97 Where are we today!!!! Where are we today!!!!? Increase in market share of antibacterial & antiviral hand antisepsis.? Convenient, Safe, Fast-acting & Environmentally-Friendly For Use Between Handwashings.? Anticepsis Hand antisepsis can interrupt virus spread.? Increasing Acceptance In U.S. & Canada.? Varied claims of efficacy of these antiseptics against a wide range of pathogens; mostly bacterial.? Activity against bacteria? Activity against viruses.? Methods to test antiseptics against viruses are available. Standard American & European Test Methods.? No Regulations to govern anti-viral claims. Where do we go from here???? Bidawid/ ASTM Washington/ Oct 2004 Health Canada

98 ? Foodhandlers We Know That.. We Know That.. Play an important role in cross-contamination Contribute to virus spread? Control measures Education Adequate food preparation practices Exclusion of ill foodhandlers from work Vaccination Bidawid/ ASTM Washington/ Oct 2004 Adequate hygienic practices & facilities - Handwashing - Antisepsis Health Canada

99 Tests Using The Fingerpad Method Tests Using The Fingerpad Method The Fingerpad Method For Virucidal Activity Is An ASTM Standard (E-1838) A Similar Method For Working With Bacteria Recently Became An ASTM Standard (E-2276) The Fingerpad Method Can Also Be Used With Fungi Such As Candida Bidawid/ ASTM Washington/ Oct 2004 Health Canada

100 Food & Environmental Virology Network Bidawid/ ASTM Washington/ Oct 2004 Health Canada

101 Label Claims of Activity Against Viruses Nilambar Biswal, Ph.D. Microbiologist Division of Antiviral Drug Products, FDA ASTM Post-Conference Symposium October 8, 2004

102 Basic Requirements for Label Claims Against Viruses Chemistry, manufacturing and controls Pharmacology/toxicology Antiviral activity Clinical data on safety and efficacy in human subjects For detailed information contact: 4/preind Phone: ASTM Post-Conference Symposium October 8, 2004

103 Virological Considerations Rationale for the proposed indication Non-clinical antiviral activity to assess risk/benefit for clinical trials Mechanism of action Antiviral activities in vitro and in vivo Drug resistance Combination therapy (synergism, antagonism or additivity Clinical Virology ASTM Post-Conference Symposium October 8, 2004

104 Antiviral Label Claims Antiviral claim for any drug product is limited to the particular virus being evaluated, since viruses may possess quite variable titers, with diverse pathogenic and transmissibility potentials Both non-clinical and clinical demonstration of the efficacy and safety of the drug is required A very limited number of topical antiseptics have been developed for and approved with antiviral claims ASTM Post-Conference Symposium October 8, 2004

105 Antiviral Label Claims (Continued) Two antiviral drug products (Denavir and Zovirax ) with topical formulations are approved against HSV infections. Abreva (a topical formulation of docosanol) was approved (as an OTC product) for the treatment of cold sores without any antiviral claim. A topical formulation of nonoxynol-9 (N-9) was not approved for the prevention of HIV transmission. ASTM Post-Conference Symposium October 8, 2004

106 Topical Antiseptics Antiseptic hand washes and skin cleansers Chemical barriers applied to skin: no gloves and under gloves Antiseptics as a coating on gloves Antiseptics packaged with condoms Antiseptics to be used in the vaginal tract ASTM Post-Conference Symposium October 8, 2004

107 Topical Antiseptics as Antivirals The Major Issues: 1. Topical antiseptic (or antimicrobial) product formulations are quite diverse (e.g., alcohols, iodines, gluconates, and xylenols) with quite variable (some without) antiviral activity. 2. Assay procedures for the inactivation of cellfree and cell-associated viruses in the presence and absence body fluids or cell debris (expected in a clinical setting) have not been adequately addressed. ASTM Post-Conference Symposium October 8, 2004

108 Topical Antiseptics as Antivirals The Major Issues (Continued) 3. Lack of experimentally defined criteria to evaluate the optimal time of exposure of any virus to any of the topical antiseptic preparations used to achieve a desirable (safe) and standardized level of reduction of virus titer in a non-clinical or clinical setting ASTM Post-Conference Symposium October 8, 2004

109 Inactivation/Reduction* Time (in Seconds)** by Topical Antiseptics Topicals Enveloped Virus Naked Virus CMV Flu Vaccinia HAV Rhino Rota Alcohol CHG > PCMX PVI > Triclosan Chlorhexidine gluconate (CHG); Parachlorametaxylenol (PCMX); Povidone Iodine (PVI); *Virus Titer =Log 10 2; **Methods of assay varied from suspension test to fingerpad methods (compiled from various published reports). ASTM Post-Conference Symposium October 8, 2004

110 Observations Naked (non-enveloped) viruses (e.g., Rotavirus and Rhinovirus) are equally susceptible as the enveloped viruses (contrary to the general expectation) to the typical topical antiseptic products. Certain active ingredients in topical antimicrobial products may not be any better than tap water in inactivating or eliminating infectious viruses. ASTM Post-Conference Symposium October 8, 2004

111 Observations Examples: 1. Aqueous solutions of chlorhexidine gluconate in common hand wash preparations was not any better than tap water against rotaviruses (Ansari et al., 1989, Appl. Environ. Microbiol. 55: ). 2. A simple rinse with water alone was more efficient in removing hepatitis A virus (HAV) than topical antimicrobial agents such as P1 and P2 in Ivory soap (Bidawad et al., 2000, Appl. Environ. Microbiol. 66: ). ASTM Post-Conference Symposium October 8, 2004

112 Observations (Continued) In a test including four antimicrobial soaps (Hibicleans, Dial, SoftSoap Antibacterial and Roccal), only two (Dial and SoftSoap Antibacterial) inactivated cell-free (but not cellassociated) vaccinia virus in a 60-second reaction period (Jonczy E.A. and Kotwal G.J., 2000, Antivir. Res. 45: ). Presence of fecal material (1) increased the survival of Rotavirus (Keswick et al., 1983, Appl. Environ. Microbiol. 46: ) and (2) protected the virus from disinfectant action (Hejkal et al., 1979, Appl. Environ. Microbiol. 38: ASTM Post-Conference Symposium October 8, 2004

113 (Continued) Observations (Continued) Routine use of antimicrobial soap and water is usually considered to be quite adequate for the decontamination of hands. Use of a less effective product may be harmful by spreading a localized contamination to both hands, thus leading to the transmission of the virus infection (Schrumann, W., and Eggers, H.J., 1985, Med. Microbiol. Immunol. 174: ; Ansari et al., 1989, Appl. Environ. Microbiol. 55: ). ASTM Post-Conference Symposium October 8, 2004

114 Summary There is an urgent need for the availability of safe and effective topical antiseptics with antiviral claims. Product formulations influence the antiviral activity Specific antiviral activity along with the therapeutic index of each ingredient (both active and inactive) in the product should be clearly defined. Synergistic, additive or antagonistic antiviral effect of any combination of ingredients in the product should be established ASTM Post-Conference Symposium October 8, 2004

115 Summary (Continued) Antiviral activities against any of the viruses (both cell-free and cell-associated) should be separately established in the presence of appropriate body fluids, excretions and injured infected tissues generally encountered in a clinical setting. The selection of appropriate assays and models will vary with product formulation, viral targets, environmental use conditions, experimental practicality, and the sensitivity and specificity of the assays. ASTM Post-Conference Symposium October 8, 2004

116 Summary (Continued) If the compound is found to be cytotoxic, the rate of virus inactivation at concentrations relevant to the proposed use should be determined. In case of highly infectious viruses, models, utilizing pig skin and/or human skin fragments, should be researched and advanced to test the antiviral activities of certain topical antiseptics. ASTM Post-Conference Symposium October 8, 2004

117 Summary (Continued) Criteria to evaluate the optimal time of exposure of viral preparations to any of the antiviral formulations used to achieve a desirable (safe) and standardized level of reduction of virus titers should be established and universally accepted. Because the antiviral efficacy and safety test results are dependent upon so many variables, human studies demonstrating safety and efficacy of topical antiviral antiseptics should continue to be required. ASTM Post-Conference Symposium October 8, 2004

118 Current Issues in Hand Hygiene in Infection Control John M. Boyce, MD Hospital of Saint Raphael New Haven, CT Clinical Professor of Medicine Yale University School of Medicine

119 Impact of Healthcare-Associated Infections Nearly 2 million healthcare-associated infections occur annually in U.S. Responsible for approx. 90,000 deaths Cost to healthcare system of > $ 1 billion

120 Major Sites of Nosocomial Infections Medical Patients Surgical Patients Richards MJ et al. ICHE 2000;21:510 UTI Pneum BSI SST EENT CVS GI SSI LRI

121 Important Healthcare-Associated Pathogens Bacterial (90 95%) Staphylococcus aureus Coag-negative staphylococci Enterococci E. coli Pseudomonas aeruginosa Klebsiella Serratia Enterobacter Acinetobacter Fungal Candida Aspergillus Viral (5 10%) * Respiratory syncytial virus Rhinovirus Adenovirus Influenza virus SARS Rotavirus Norovirus Astrovirus Enteroviruses Hepatitis A Hepatitis B and C HIV * Viruses cause 32% of nosocomial infections in children

122 Relative Frequency of Respiratory Viruses Parainfluenza 12% Respiratory Syncytial Virus 11% Rhinovirus 35% Influenza 30% Other 4% Adenovirus 8% Monto AS Am J Med 2002;112;(6A):4S

123 Modes of Transmission of Respiratory Viruses Contact transmission Direct Indirect Droplet transmission Large droplets generated by sneezing, coughing, or talking Occurs over distance of 3-4 feet Airborne transmission Due to small droplet nuclei Occurs over many feet

124 Respiratory Syncytial Virus > 90,000 young children are hospitalized annually in the U.S. due to RSV infections 450 children die from RSV infection annually > 50% of medical staff on pediatric wards become infected with RSV during seasonal peaks Young children, visitors and hospital staff can act as sources of nosocomial spread of RSV Hall CB J Pediatr 1999;136:S2 Hall CB Clin Infect Dis 2000;31:590

125 Nosocomial Transmission of Respiratory Syncytial Virus Prospective study of RSV transmission in a hospital nursery Personnel were divided into 3 groups Cuddlers: direct care of infant for 2-4 hrs wore gown, but no mask or gloves Touchers: touched potentially contaminated objects (e.g., toys, crib sides, pacifiers) in infant s room while the infant was not present then, touched mucous membranes of nose or eye Sitters: sat more than 6 feet from infants bed wore gowns and gloves, but no mask Nasal cultures of staff were obtained q 2-3 days Hall CB and Douglas GD J Pediatr 1981;99:100

126 Nosocomial Transmission of Respiratory Syncytial Virus RSV infection developed in 5 (71%) of 7 cuddlers 4 (40%) of 10 touchers 0 of 14 sitters Nosocomial transmission of RSV may occur by Close contact with direct inoculation of large droplets droplet transmission Self-inoculation after touching contaminated surfaces indirect contact transmission Hall CB and Douglas GD J Pediatr 1981;99:100

127 Modes of Transmission of Respiratory Viruses in Healthcare Facilities Medical personnel were observed during a conference in an auditorium 68 person-hrs of observation revealed 28 episodes of nose-picking 23 episodes of rubbing eyes with fingerpads Opportunities for selfinoculation occur commonly among medical personnel Courtesy: D. Pittet, MD University of Geneva Hospitals Hendley JO et al. N Engl J Med 1973;288:1361

128 Transmission of Rhinoviruses Rhinovirus is shed in large amounts in the nasal secretions of patients with rhinovirus colds 40% of affected individuals contaminate their hands with rhinovirus Rhinovirus can survive on human skin for 2-3 hrs on non-porous environmental surfaces for 3 hrs Hendley JO et al. N Engl J Med 1973;288:1361

129 Experimental Transmission of Rhinovirus Hand to Hand Large Particle Small Particle (Direct Contact) (Droplet) (Airborne) Donor purposely contaminated hands with nasal secretions Recipients touched donors hands with their fingers x 10 sec Recipients purposely placed their fingers on nasal and conjunctival mucosa Both donor and recipient wore masks while in contact Donor and 2-4 Recipients sat around Table x 15 min Donor talked loudly, Sang, coughed and Sneezed Donors and recipients Wore rubber gloves Donors and recipients Spent 3 days together In a large, closed room Donors were separated From recipients by a Double wire-mesh Barrier than prevented Any physical contact Infection: 73% Infection: 8% Gwaltney JM et al. Ann Intern Med 1978;88:463 Infection: 0/10

130 Global SARS Epidemic In the SARS epidemic, spread often occurred in hospitals Nosocomial transmission accounted for 72% of cases in Toronto 55% of cases in Taiwan 20% of cases affected HCWs (44% in Toronto) Transmitted occurred by: respiratory droplets direct contact possibly airborne route McDonald LC et al. Emerg Infect Dis 2004;10:777

131 Established Causes of Nosocomial Diarrhea in a Pediatric/Women s Hospital Diarrhea was the 3rd most common nosocomial infection in children 122 (56%) of episodes had an identifiable cause Adenovirus 30% Other viruses 7% C. difficile 32% Viral diarrhea was most common in children < 2 y/o Rotavirus 31% Langley JM et al. Infect Control Hosp Epidemiol 2002;23:660

132 Rotaviruses Worldwide: 600,000 deaths annually in children In United States: 55,000 hospitalizations/year $ 1 billion/year in medical & nonmedical costs Transmitted by fecal-oral route ingestion of contaminated food or water contact with contaminated surfaces or stool Important cause of nosocomial gastroenteritis Causes outbreaks as well as endemic disease

133 Noroviruses 23 million cases of gastroenteritis/year Responsible for 50% of foodborne outbreaks Person-to-person transmission also important Cause outbreaks related to restaurants, catered meals nursing homes hospitals schools cruise ships

134 Astroviruses 5-year prospective of diarrhea in hospitalized children 19% of children had diarrhea on admission or developed nosocomial diarrhea Astroviruses were 2nd only to rotavirus as a cause of community-acquired and nosocomial diarrhea caused 12% of episodes of nosocomial diarrhea Dennehy PH et al. J Infect Dis 2001;184:10

135 Herpes Family of Viruses Herpes simplex virus is transmitted from patients to healthcare workers hands Varicella-zoster virus (causes shingles ) can be transmitted from patients to healthcare workers HSV Cytomegalovirus is occasionally transmitted from patients to VZV

136 Hepatitis A Important cause of foodborne infection Rarely causes nosocomial outbreaks affecting healthcare workers Transmitted by food or by fecal-oral route (contact transmission)

137 Bloodborne Pathogens Hepatitis B, hepatitis C and HIV are serious causes of occupational illness acquired by healthcare workers Acquired following exposure to blood or body fluids contaminated with blood percutaneous exposures are most common cause rare cases due to contamination of mucous membranes Can have life-long effects on health of HCW

138 Viral Hemorrhagic Fever Agents Occur primarily in Africa High mortality rate (50%) including nurses/doctors Occasional cases are imported into U.S. (8/2004) Possible bioterrorism agents

139 Smallpox: A Bioterriorism Agent

140 Modes of Transmission of Viruses Implicated in Nosocomial Transmission Virus Contact Transmission Droplet RSV + + Rhinovirus + + Parainfluenza? +? + Adenovirus + + Influenza? + + SARS coronavirus? + + Metapneumovirus?? Rotavirus + Astrovirus + Norovirus + Enterovirus + Herpes simplex virus + Hepatitis A + Hepatitis B & C percutaneous exposure HIV percutaneous exposure Lassa Fever +? + Ebola +? + Smallpox + +

141 HCW Handwashing Adherence PHS CDC APIC APIC Movie HWG HWG HHG 90 Percent

142 Factors Influencing Handwashing Adherence Prospective study involving > 2800 observations Data analyzed by multivariate analysis Factors associated with poor compliance: When intensity of care was high (high work loads) Not enough time to wash hands frequently Job category: MDs (30%) -> Nurses (52%) Weekdays Intensive care units During procedures with high risk of contamination Pittet D et al. Ann Intern Med 1999;130:126

143 Are Recommended Handwashing Policies Practical? Time required for soap & water handwashing: 62 seconds to get to sink, wash, dry and return 10-second scrub ICU with 12 nurses 40% compliance: 2 to 6.4 hrs/shift 100% compliance: 16 hrs/shift Time required for alcoholic hand disinfection: 15-second contact time bedside dispenser 40% compliance: 1 to 1.6 hrs/shift 100% compliance: 4 hrs/shift Voss A & Widmer AF ICHE 1997;18:205-8

144 OTHER FACTORS ADVERSELY AFFECTING HANDWASHING COMPLIANCE Poor access to sinks and handwashing facilities

145 Other Factors Adversely Affecting Handwashing Adherence Irritant contact dermatitis due to frequent handwashing

146 Skin Irritation and Dryness: Soap & Water Handwashing vs Alochol Hand Gel A prospective randomized trial with crossover design 29 nurses working on 3 wards participated The study compared: A non-medicated, mild soap An alcohol hand gel Alcohol hand gel dispensers were placed outside each patient s room, or in the patient s cubicle (ICU) Skin irritation/dryness of nurses hands were assessed: self-assessment by participants visual assessment by study nurse electrical capacitance of skin on hands Boyce JM et al. Infect Control Hosp Epidemiol 2000;21:442

147 Electrical Capacitance of Dorsal Hand Skin Surface Mean Corneometer Reading N = 29 Baseline Middle Final Soap Alcohol Gel Boyce JM et al. Infect Control Hosp Epidemiol 2000;21:442

148 Hand Hygiene Compliance During 7 Hospital-Wide Surveys, University of Geneva Hospitals, Percent Compliance Hand disinfection Handwashing Pittet D et al. Lancet 2000;356:1307

149 Prevalence of Nosocomial Infections and Incidence of MRSA, University of Geneva Hospitals, New MRSA Cases/100 Adm Nosocomial Infections/100 Adm Nosocomial Infections MRSA Cases Pittet D et al. Lancet 2000;356:1307

150 Advantages of alcohol-based hand rubs When compared to traditional soap and water handwashing, alcohol-based hand rubs have the following advantages: take less time to use can be made more accessible than sinks cause less skin irritation and dryness are more effective in reducing bacteria on hands making alcohol-based hand rubs readily available to personnel has led to improved hand hygiene practices

151 Hand Hygiene Guideline Extensive literature review was conducted, and a new evidence-based guideline was submitted for public comment Input from FDA, included revised wording related to activity of agents against viruses In October 2002, the HICPAC/SHEA/APIC/IDSA Hand Hygiene guideline was Published in MMWR Boyce JM, Pittet D et al. MMWR 2002;51(RR-16)

152 Hand Hygiene Guideline Exposure to healthcare workers to variety of viral pathogens warranted a discussion of antiviral activity of hand antiseptic agents Discussion of antiseptic agents included information about in vitro evidence of antiviral activity results of in vivo testing (finger pad method) mimics conditions under which products will be used by healthcare workers controls for differing survival of viruses on skin

153 Unresolved Issues Which strategies are most effective in improving adherence of healthcare workers to recommended hand hygiene policies What level of efficacy (Log Reductions) is necessary to effectively reduce transmission of healthcare-associated pathogens Are formulations with persistent activity any more effective in reducing nosocomial transmission than those without Compared to EN standards, current US regulations appear to make development of formulations containing > 1 active agent very expensive

154 THE ROLE OF HANDS IN THE SPREAD OF NOSOCOMIAL VIRAL INFECTIONS YED A. SATTAR, Ph.D. IRECTOR ENTRE FOR RESEARCH ON ON NVIRONMENTAL MICROBIOLOGY (CREM) NIVERSITY OF OF OTTAWA, OTTAWA, ON, ON, CANADA CREM CRME CREM WEBSITE:

155 OUTLINE IMPACT OF INFECTIONS ON HUMAN HEALTH WHAT ARE NOSOCOMIAL INFECTIONS? WHAT ARE VIRUSES? HOW IMPORTANT ARE THEY AS AS HUMAN PATHOGENS? IS IS THEIR THEIR SIGNIFICANCE CHANGING? HOW IMPORTANT ARE THEY AS AS NOSOCOMIAL PATHOGENS? HOW DO DO THEY SPREAD IN IN NATURE? WHAT IS IS THE RELATIVE IMPORTANCE OF HANDS IN IN THE SPREAD OF VIRUSES? WHERE DO WE GO FROM HERE? SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

156 KNOWN SPECIES OF HUMAN PATHOGENS (TAYLOR (TAYLOR ET ET AL. AL. PHIL. PHIL. TRANS. TRANS. R. R. SOC. SOC. LOND. LOND. B. B. 2001; 2001; 356: ) 356: ) A COMPREHENSIVE LITERATURE- BASED INVENTORY OF HUMAN PATHOGENS (UNIV. OF EDINBURGH) 61% (868/1415) ARE ZOONOTIC 175 SPECIES ARE CONSIDERED EMERGING; 75% (132/175) OF THESE ARE ZOONOTIC ROUTE(S) OF SPREAD OF >200 HUMAN PATHOGENS UNKNOWN!! BACTERIA VIRUSES & PRIONS FUNGI PROTOZOA HELMINTHS TOTAL SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

157 IMPACT OF INFECTIOUS DISEASES GLOBALLY, INFECTIOUS DISEASES CAUSE >32% >32% (18 (18 MILLION) OF OF THE THE MILLION FATALITIES/YEAR (WHO (WHO 2001) 2001) Other Other causes causes 68.1% 68.1% (37.9 (37.9 million) million) >40 NEW PATHOGENS DISCOVERED IN IN PAST YEARS ALONE (DESSELBERGER, (DESSELBERGER, J. J. INFECT. INFECT. 2000; 2000; 40:3-15) 40:3-15) INFECTIONS LEAD TO 19% (~130 MILLION) OF VISITS TO Infectious Infectious diseases diseases 31.9% 31.9% (17.8 (17.8 million) million) PHYSICIANS/YEAR (ARMSTRONG (ARMSTRONG& PINNER, PINNER, 1999) 1999) EXPANDING ROLE OF INFECTIOUS AGENTS IN IN DISEAS SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

158 WHAT IS IS A NOSOCOMIAL INFECTION? AN N INFECTION OCCURRING IN IN A PATIENT IN IN A HOSPITAL OR OR THER HEALTH CARE FACILITY IN IN WHOM THE INFECTION WAS OT OT PRESENT OR OR INCUBATING AT AT THE TIME OF OF ADMISSION. HIS INCLUDES INFECTIONS ACQUIRED IN IN THE HOSPITAL BUT PPEARING AFTER DISCHARGE, AND ALSO OCCUPATIONAL FECTIONS AMONG STAFF OF OF THE FACILITY. FROM: FROM: A.S. A.S. BENENSON BENENSON (1995). (1995). CONTROL CONTROL OF OF COMMUNICABLE COMMUNICABLE DISEASES DISEASES MANUAL, MANUAL, th th EDITION EDITIO WASHINGTON, WASHINGTON, AMER. AMER. PUB. PUB. HLTH. HLTH. ASSOC ASSO SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

159 BASIC STRUCTURE OF A VIRUS PARTICLE (VIRION) PROTEIN SHELL (CAPSID) ADENOVIRUS ADENOVIRUS (NON-ENVELOPED) (NON-ENVELOPED) PROTEIN-LIPID ENVELOPE INFLUENZAVIRUS INFLUENZAVIRUS (ENVELOPED) (ENVELOPED) NANOMETERS ULTRA-MICROSCOPIC OBLIGATE PARASITES NUCLEIC ACID (( DNA OR OR RNA) GENOME SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

160 IMPORTANCE OF VIRUSES AS PATHOGENS MAJOR CAUSES OF OF MORTALITY & MORBIDITY COMMON IN IN RESPIRATORY & ENTERIC INFECTIONS MANY NEWLY FOUND PATHOGENS ARE VIRUSES! SIGNIFICANT ROLE IN IN FOODBORNE DISEASE IN IN U.S., >5% OF OF NOSOCOMIAL CASES DUE TO TO VIRUSES; ABOUT 32% IN IN PEDIATRIC SETTINGS LACK OF OF NEW VACCINES & DRUGS IMMUNOSUPPRESSION REACTIVATES LATENT VIRUSES INCREASES SUSCEPTIBILITY TO TO NOSOCOMIAL VIRUSES RELATIVE IMPORTANCE INCREASING!! SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

161 INCREASING HEALTH IMPACT OF VIRUSES CHRONIC CONDITIONS ARTERIOSCLEROSIS (VALANTINE. (VALANTINE. AM. AM. J. J. TRANSPLANT. TRANSPLANT. 2004; 2004; 4: ) 4: ) ARTHRITIS (SUHRBIER (SUHRBIER & LA LA LINN. LINN CURR CURR OPIN OPIN RHEUMATOL. RHEUMATOL. 16: ) 16: ) EXACERBATION OF OF ASTHMA (JACOBY. (JACOBY. J. J. AEROSOL. AEROSOL. MED. MED : ) 17: ) CANCERS (WHO (WHO 2003) 2003) POLYMICROBIC DISEASES: ~15% OF OF ACUTE OTITIS MEDIA CASES A MIXTURE OF OF VIRUSES & BACTERIA (HEIKKINEN (HEIKKINEN & CHONMAITREE. CHONMAITREE. CLIN. CLIN. MICROBIOL. MICROBIOL. REV. REV. 2003; 2003; 16: ) 16: ) VIRUSES & OBESITY (DHURANDHAR, (DHURANDHAR, J. J. NUTR. NUTR. 2001; 2001; 131:2794S-2797S) 131:2794S-2797S) BEHAVIORAL CHANGES, E.G. BORNAVIRUS (BODE (BODE & LUDWIG, LUDWIG, CLIN CLIN MICROBIOL MICROBIOL REV. REV. 2003;16: ) 2003;16: ) APPEARANCE OF OF DELAYED DAMAGE (TABLE) (TABLE) SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

162 VIRUSES & DELAYED DAMAGE CAUSED VIRUS Polioviruses Papillomaviruses Hepatitis B virus Hepatitis C virus Rubella virus DELAYED DAMAGE Post-polio syndrome Genital cancers Hepatocellular carcinoma Hepatocellular carcinoma Congenital malformations SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT. 2004

163 SPREAD OF VIRUSES IN IN HEALTHCARE SETTINGS SOURCE OF VIRUS ENVIRON. SURFACES WATER FOOD INSECTS MEDICAL DEVICES AIR HANDS SUSCEPTIBLE HOST SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

164 SOURCES OF EXOGENOUS AND ENDOGENOUS VIRAL CONTAMINATION ON HANDS FOMITES & CLOTHES & OTHER HANDS & ENVIRONMENTAL OTHER SURFACES FABRICS BODY BODY SURFACES CLINICAL & LAB LAB MATERIALS SOIL SOIL BODY BODY SECRETIONS & EXCRETIONS ANIMALS FOOD FOOD WATER MEDICAL DEVICES SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

165 SURVIVAL OF OF SELECTED PATHOGENS ON ON THE THE HANDS OF OF ADULTS AFTER AFTER ONE ONE HOUR HOUR (MODIFIED (MODIFIED & & UPDATED UPDATED FROM FROM SATTAR SATTAR ET ET AL. AL. 1996) 1996) TEN µl OF THE TEST ORGANISM IN A SOIL LOAD WAS PLACED ON THE FINGERPADS OF ADULT SUBJECTS. THE INOCULUM WAS ELUTED AFTER 1 HOUR & THE ELUATES TITRATED FOR VIABLE ORGANISMS Canine Parvo Hepatitis A Rota S. aureus Rhino Feline Calici Adeno E. coli Paraflu 3 SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

166 SURVIVAL OF OF CORONAVIRUS 229E ON ON HANDS OF OF ADULTS TIME IN MINUTES SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

167 WHERE ARE VIRUSES RELEVANT? VIRUSES NOT A PART OF BODY S NORMAL MICROFLORA LOW RELEVANCE FOR: PRE-OPERATIVE SKIN PREPS & SURGICAL SCRUBS HIGH RELEVANCE IN: HOSPITALS, NURSING HOMES & DAYCARE COMMERCIAL FOOD PREPARATION & SERVING ESTABLISHMENTS HOME CARE DOMESTIC SETTINGS VAGINAL GELS SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

168 WHICH VIRUSES ARE IMPORTANT? NON-ENVELOPED ADENOVIRUSES (CONJUNCTIVITIS) ASTROVIRUSES (ACUTE DIARRHEA) CALICIVIRUSES (ACUTE DIARRHEA) ENTEROVIRUSES (FEVER, RASH, ETC.) HEPATITIS A VIRUS (LIVER INFECTION) PAPILLOMAVIRUSES (WARTS, CANCERS) PARVOVIRUSES (ANIMAL HEALTH) RHINOVIRUSES (COMMON COLD) ROTAVIRUSES (ACUTE DIARRHEA) ENVELOPED (?) SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

169 GLOBAL HEALTH IMPACT OF OF ROTAVIRUSES (PARASHAR (PARASHAR ET ET AL. AL. EMERG. EMERG. INFECT. INFECT. DIS. DIS. 2003; 2003; 9: 9: ) ) VISITS TO CLINICS (1:5) EVENT (RISK) EPISODES OF DIARRHEA REQUIRING HOME CARE (1:1) NUMBER/YEAR IN MILLIONS HOSPITALIZATIONS (1:65) DEATHS IN CHILDREN <5 YEARS (1:293) 2 ~0.5 SAFE & EFFECTIVE VACCINE STILL UNAVAILABLE PERSONAL & ENVIRONMENTAL HYGIENE EFFECTIVE IN IN PREVENTING SPREAD OF OF ROTAVIRAL INFECTIONS RELATIVE IMPORTANCE OF OF VARIOUS VEHICLES? SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

170 TENTATIVE FINAL MONOGRAPH NO MENTION OF VIRUSES! PUBLIC WORKSHOP OF MAY-JUNE 1994 PETITION OF JAN. 17, 2003 (CTFA/SDA) LETTER OF JUNE 22, 2004, TO DR. L.M. CRAWFORD, A/COMMISSIONER OF FDA THIS ASTM SYMPOSIUM SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

171 CONCLUDING REMARKS VIRUSES CONTINUE TO BE A MAJOR HEALTH PROBLEM HANDS ARE IMPORTANT IN IN VIRAL SPREAD DISEASE PREVENTION THROUGH ENVIRONMENTAL CONTROL & HYGIENE IS IS MAKING A COMEBACK!! BETTER KNOWLEDGE OF PATHOGEN SPREAD & DESIGN OF RATIONAL CONTROL MEASURES NEEDED GLOBAL AGREEMENT NEEDED ON TEST METHODOLOGY SURROGATES, PRODUCT PERFORMANCE CRITERIA CANADA HAS STARTED PRODUCT REGISTRATION! SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

172 RECOMMENDATIONS U.S. FDA SHOULD SOON REVISIT ISSUE OF LABEL CLAIMS AGAINST VIRUSES FOR FORMULATIONS TO BE USED IN: NOSOCOMIAL SETTINGS FOOD HANDLING ESTABLISHMENTS NEED FOR FIELD STUDIES TO DEMONSTRATE PRODUCT EFFECTIVENESS THROUGH CLINICAL STUDIES BE REVIEWED ANY DECISIONS TAKEN BE IN IN LINE WITH OTHER NATIONAL & INTERNATIONAL JURISDICTIONS SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

173 ACKNOWLEDGMENTS ASTM INTERNATIONAL KATHY BAXTER KHALID IJAZ JOHN MITCHELL DAN SMITH STAFF & STUDENTS AT CREM SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

174 FOOD FOR THOUGHT THE REALITY IS, WE RE FACING UNTREATABLE INFECTIONS IN OUR HOSPITALS FOODBORNE ILLNESS HAS BECOME ONE OF THE FASTEST- GROWING COMMUNITY-HEALTH PROBLEMS TO ME THESE THINGS ARE OF MUCH GREATER CONCERN THAN SOMETHING TERRIBLE FROM THE JUNGLE. --Dr. Dr. M. M. Cohen, CDC s National Center for for Infect. Diseases (Fall, 1996 SYED A. A. SATTAR, HANDS & NOSOCOMIAL VIRUSES, ASTM, OCT

175 Proceedings of the First Workshop on Antiviral Claims for Topical Antiseptics- A Summary Albert T. Sheldon, Jr. Ph.D. Antibiotic and Antiseptic Consultants, Inc.

176 Purpose of Workshop To address various problems and prospects of developing and testing topical antiseptics for their ability to inactivate cell free and cell-associated viruses. To provide researchers and drug manufactures a strategic approach for the development and marketing of effective topical antiviral antiseptics. ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 2

177 Strategic Nonclinical Antiviral Drug Product Development-CDER Mechanism of Action-enveloped vs. nonenveloped viruses Intended Viral Targets-in vitro/in vivo spectrum, surrogate Virus Concentration/Inactivation Kinetics Product Formulation-active vs. inactive Validation of Test Methods-In vitro & Animal models Selection of viruses Endpoints of virus inactivation Sensitivity and specificity of assays Neutralization Temperature and ph Organic Load ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 3

178 Clinical Trials Because of regulatory requirements, some form of clinical trial required to demonstrate efficacy. Trial design dependent on labeling claim. Claims for treatment or prevention of disease requires clinical efficacy and safety studies in patients. Claims of reducing contamination or viruses on skin surface requires demonstration in human subjects. ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 4

179 Issues Discussed Methods not standardized, surrogate viruses not validated, and validated pass/fail criteria do not exist. Requirements for antiseptics (CDER) and disinfectants (CDRH) differ. Agency relies of collective body of evidence to assess efficacy as described in previous slides. ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 5

180 Issues Discussed Drug development focus on viruses of Public Health Concern. Labeling Claims Pros and Cons of virus specific vs. general virucidal labeling claims Consumer vs. professional Hand wash, topical wound agents, and vaginal product requirements discussed simultaneously. ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 6

181 Conclusions Agency will use the tier approach for antiviral drug product development of antiseptics. Information gathered from tier approach used to develop surrogate models. Agency encourages further research and submission of data to help address issues. ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 7

182 Question to the FDA What advances have been made by the agency to address or advance issues and thoughts presented during the 1994 workshop? ASTM Symposium October 8, 2004 Antibiotic and Antiseptic Consultants, Inc. 8

183 The OTC Monograph Process Debbie Lumpkins Division of OTC Drug Products October 8, 2004

184 The OTC Monograph Process What is the OTC Drug Review? Who is eligible? What are the basic principles of the review? How does the process work? What is a citizen petition, and what is its impact on the monograph process? ASTM Post-Conference Symposium October 8, 2004

185 What is the OTC Drug Review? ASTM Post-Conference Symposium October 8, 2004

186 What is the OTC Drug Review? Retrospective review of the safety and effectiveness of OTC products on the market prior to May 11, 1972 (extended to December 4, 1975) Initiated to evaluate all OTC drug products not approved by FDA and those approved based only on safety prior to 1962 ASTM Post-Conference Symposium October 8, 2004

187 What is the OTC Drug Review? Federal Food, Drug & Cosmetic Act Historical Context 1938 Safety requirement Durham-Humphrey Amendments Kefauver-Harris Amendments Rx/OTC distinction Efficacy requirement Drug Efficacy Study Implementation (DESI) 1964 Evaluation of pre62 drugs ASTM Post-Conference Symposium October 8, 2004 OTC Drug Review 1972

188 What is the OTC Drug Review? Evaluation by drug product categories rather than by individual products Public notice and comment rulemaking Multistage process Procedure and standards are described in 21 CFR Determination general recognition of the safety and effectiveness ASTM Post-Conference Symposium October 8, 2004

189 What is the OTC Drug Review? End product is a regulation in 21 CFR parts 331 to 358 defining: Safe and effective active ingredients Acceptable use concentrations Combinations of active ingredients Labeling Final formulation testing ASTM Post-Conference Symposium October 8, 2004

190 Who is eligible? ASTM Post-Conference Symposium October 8, 2004

191 ASTM Post-Conference Symposium October 8, 2004 Who is Eligible? Definition of an OTC A drug shall be permitted for OTC sale unless it may only be safely sold and used under a practitioners prescription because of: Toxicity or other potential for harmful effect Method of use Other collateral measures necessary for its use

192 Who is eligible? Initially, products were accepted into the review regardless of the marketing history Products or similarly formulated and labeled products marketed in the US prior to December 4, 1975 Products that can demonstrate a significant history of OTC use outside US as described in 21 CFR ASTM Post-Conference Symposium October 8, 2004

193 Who is eligible? Time and extent procedures (21 CFR ) Marketed for OTC purchase by consumers Demonstrate that pharmacy only marketing doesn t indicate a safety concern Minimum 5 years of continuous marketing in the same country and in sufficient quantity Submission of a time and extent application ASTM Post-Conference Symposium October 8, 2004

194 What are the basic principles of the review? ASTM Post-Conference Symposium October 8, 2004

195 What are the Basic Principles? Safety 21 CFR (a)(4)(i) Low incidence of adverse reactions or significant side effects when used according to label directions Low potential for abuse under conditions of wide availability ASTM Post-Conference Symposium October 8, 2004

196 What are the Basic Principles? Proof of Safety 21 CFR (a)(4)(i) Adequate tests under conditions of use Results of significant human marketing experience Published studies May be corroborated by unpublished data ASTM Post-Conference Symposium October 8, 2004

197 What are the Basic Principles? Effectiveness 21 CFR (a)(4)(ii) A reasonable expectation that in a significant proportion of the population, the pharmacological effect of the drug will provide clinically significant relief of the type claimed when used according to label directions and warnings ASTM Post-Conference Symposium October 8, 2004

198 What are the Basic Principles? Proof of effectiveness (21 CFR (a)(4)(ii) Adequate and well controlled clinical trials described in 21 CFR (b) Requirement may be waived if shown that such studies are not reasonably applicable to the drug or critical to its evaluation and alternate methods of investigation are adequate Generally published studies ASTM Post-Conference Symposium October 8, 2004

199 What are the Basic Principles? Unacceptable as evidence of effectiveness 21 CFR (a)(4)(ii) Isolated case reports Random experience Data lacking details sufficient to permit scientific evaluation ASTM Post-Conference Symposium October 8, 2004

200 What are the Basic Principles? Risk/Benefit 21 CFR (a)(4)(iii) Evaluation of the categorization will include an assessment of the benefit-torisk ratio for the product ASTM Post-Conference Symposium October 8, 2004

201 What are the Basic Principles? Combinations 21 CFR (a)(4)(iv) Two or more actives may be combined Each active must make a contribution to the claimed effect Combining does not decrease the safety and effectiveness of any of the active ingredients Combination provides rational concurrent therapy for a significant proportion of the target population ASTM Post-Conference Symposium October 8, 2004

202 What are the Basic Principles? Labeling 21 CFR (a)(4)(v) Clear and truthful Not false or misleading Intended uses and results Adequate warnings against unsafe use or side effects Use terms likely to be read and understood by ordinary individuals ASTM Post-Conference Symposium October 8, 2004

203 What are the Basic Principles? Monograph classifications Category I generally recognized as safe and effective Category II not generally recognized as safe and effective Category III insufficient data available to permit final classification ASTM Post-Conference Symposium October 8, 2004

204 How does the process work? ASTM Post-Conference Symposium October 8, 2004

205 How Does the Process Work? Call for data Panel Report FDA s Proposal Final Rule Compliance ASTM Post-Conference Symposium October 8, 2004

206 How Does the Process Work? Time and Extent Applications (TEA) Application Notice of eligibility Call for data Denial FDA Proposal Final rule ASTM Post-Conference Symposium October 8, 2004

207 How Does the Process Work? Each step published in the Federal Register Opportunity for comment, submission of new data, and comments on new data and information FDA evaluates and responds to comments and submitted data in the preamble of the regulation The regulation reflects the Panel recommendations and FDA s responses to the comments and data ASTM Post-Conference Symposium October 8, 2004

208 How does the process work? Marketing prior to a final rule Products included in the review may continue to market prior to a final rule Marketing is subject to the risk that product will need to be brought into compliance with a final rule Marketing of TEA products can only occur with the publication of an enforcement policy or a final rule ASTM Post-Conference Symposium October 8, 2004

209 How Does the Process Work? Marketing after a FR Compliance with a final rule is required by its effective date Compliant products require no preclearance to market Nonmonograph products are new drugs that require preclearance for marketing ASTM Post-Conference Symposium October 8, 2004

210 What is a citizen petition, and what is its impact on the monograph process? ASTM Post-Conference Symposium October 8, 2004

211 What is a Citizen Petition? Request for FDA to take an action or refrain from taking an action Described in 21 CFR Public Opportunity for public comment May be submitted at any time during or after the OTC rulemaking process ASTM Post-Conference Symposium October 8, 2004

212 What is a Citizen Petition? 21 CFR (7)(v) Comments submitted after the close of the comment period of a proposal but prior to a final rule Petition to amend the final rule May be considered as part of the rulemaking with good cause ASTM Post-Conference Symposium October 8, 2004

213 What is the Impact on the Monograph Process? Proposal Citizen petition Final Rule Proposal Proposal Final rule ASTM Post-Conference Symposium October 8, 2004

214 Healthcare Antiseptic Panel Report 1974 A case study FDA s proposal 1978 Six citizen petitions Reopening 1979 Data submitted after close of comment Reopening period 1980 ASTM Post-Conference Symposium October 8, 2004

215 Healthcare Antiseptic Two reopenings 1982 A case study Decision to split consumer and healthcare antiseptics Into separate rulemakings FDA proposal healthcare antiseptics 1994 FDA proposal first aid antiseptics 1991 ASTM Post-Conference Symposium October 8, 2004

216 Healthcare Antiseptic FDA Proposal Healthcare antiseptics 1994 A case study 16 citizen petitions Reopening 1994 Additional data and citizen petitions ASTM Post-Conference Symposium October 8, 2004

217 The OTC Monograph Process In summary Complex interactive public process Because of its interactive nature it is not the quickest ASTM Post-Conference Symposium October 8, 2004

218 METHODS FOR TESTING ACTIVITY OF TOPICALS AGAINST VIRUSES: U.S. AND GLOBAL PERSPECTIVE M. Khalid Ijaz, D.V.M., Ph.D. Director and Vice President Division of Aerobiology, Protozoology and Virology MICROBIOTEST, INC., Sterling, VA and Affiliate Professor Department of Molecular and Microbiology George Mason University, Fairfax, VA Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

219 OUTLINE VIRUSES, PUBLIC HEALTH AND HAND HYGIENE: HISTORICAL PERSPECTIVE MAJOR FACTORS IN TESTING THE ANTIVIRAL ACTIVITY OF HANDWASH & HANDRUB AGENTS IN VIVO TESTING OF TOPICALS TESING OF HYGIENIC HANDWASH AGENTS AGAINST VIRUSES IN VIVO THE FINGERPAD METHOD AND DATA GENERATED AT MICROBIOTEST ISSUES, RECOMMENDATIONS AND CONCLUDING REMARKS ACKNOWLEDGEMENTS Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

220 Major Etiological Agents of Infectious Diseases Identified since 1972* Over the > 30 years, a number of emerging and re-emerging viruses has dominated the scientific literature. In 70s, enteric (rotavirus, Norwalk), Ebola, Hantaan viruses In 80s, retroviruses including HIV AIDS and hepatitis C In 90s, Sin Nombre, HEV, HGV, HFV, Nipah & Hendra, West Nile viruses and Prion) In 2000s, FMDV, avian influenza, SARS-HCoV (Partly from Desselberger, 2000 FACTORS PREDISPOSING TO SPREAD OF NEW, EMERGING AND RE- EMERGING VIRAL DISEASES INCLUDE BUT NOT LIMITED TO GLOBAL TRAVEL AND MASS MOVEMENTS, HUMAN DEMOGRAPHICS AND BEHAVIOUR, VIRAL GENOME CHANGE AND ADAPTATION AND ANIMAL HUSBANDRY INTENSIFICATION ETC. Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

221 VIRUSES, PUBLIC HEALTH AND HAND HYGIENE: HISTORICAL PERSPECTIVE FOLLOWING HISTORICAL INTERVENTION TRIALS BY SEMMELWEIS IN VIENA, A NUMBER OF INTERVENTION TRIALS HAVE BEEN SHOWN TO REDUCE THE RISK OF INFECTION. VIRUSES ARE IMPORTANT ETIOLOGIC AGENT FOR MORBIDTY AND MORTALITY GLOBALLY. NEW EMERGING AND RE-EMERGING VIRUSES ARE ON THE RISE (WEST NILE, SARS-HCoV). IN THE US 5% OF NOSOCOMIAL CASES DUE TO VIRUSES, ~32% IN PEDIATRIC, of which RSV was most common (Aitken and Jeffries, 2001) Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

222 VIRUSES, PUBLIC HEALTH AND HAND HYGIENE: HISTORICAL PERSPECTIVE (cont d) HANDS PLAY AN IMPORTANT ROLE IN THE SPREAD OF MANY VIRAL INFECTIONS AND PROPER HAND WASHING BY CAREGIVERS, FOOD HANDLERS FOR INTERRUPTION OF SPREAD OF VIRUSES AND OTHER TYPES OF PATHOGENS IS UNIVERSALLY RECOGNIZED THIS HAS BEEN DEMONSTRATED IN INTERVENTION EXPERIMENTAL AS WELL AS STUDIES CONDUCTED IN CLINICAL SETTINGS (Black et al., 1981, Hendley & Gwaltney, 1988; Ward et al., 1991) INFECTIOUS VIRUS HAVE BEEN RECOVERED FROM NATUALLY CONTAMINATED HANDS. CASES IN POINT HCV, RSV, RHINO-, ROTAVIRUSES (Alfurayh et al., 2000; Hall & Douglas, 1981; Keswick et al., 1983 and Hendley & Gwaltney, 1988) Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

223 VIRUSES, PUBLIC HEALTH AND HAND HYGIENE: HISTORICAL PERSPECTIVE (cont d) Although the FDA Center for Food Safety and Nutrition (CFSAN) recognize the significance of viruses being disseminated by food handlers and healthcare worker and role played by hands in this regard, the Tentative Final Monograph (TFM) of FDA does not address viruses at all. PROPER ANTISEPTICS PROCEDURES FOR USED DECONTAMINATION OF HANDS CAN INTERRUPT SUCH DISSEMINATION Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

224 MAJOR FACTORS IN IN TESTING THE ANTIVIRAL ACTIVITY OF OF HANDWASH & HANDRUB AGENTS USE USE IN IN VITRO VITROCARRIER TESTING TESTING ONLY ONLY AS AS A SCREEN SCREEN (SKIN (SKIN TEMPERATURE, TEMPERATURE, TOPOGRAPHY TOPOGRAPHY & DYNAMIC DYNAMIC NATURE NATURE OF OF SKIN) SKIN) SELECT SELECT PANELISTS PANELISTS WITH WITH STRICT STRICT INCLUSION/EXCLUSION CRITERIA CRITERIA & AFTER AFTER RECEIVING RECEIVING INFORMED INFORMED CONSENT CONSENT GIVE GIVE PANELISTS PANELISTS PRODUCTS PRODUCTS FOR FOR WASH-OUT WASH-OUT PERIOD PERIOD CHOOSE CHOOSE QUANTITATIVE QUANTITATIVE IN IN VIVO VIVOMETHODS FOR FOR REPRODUCIBLE REPRODUCIBLE DATA DATA WITH WITH PRECISE PRECISE LOG LOG 10 REDUCTIONS 10 REDUCTIONS EXPOSE EXPOSE INTACT INTACT SKIN SKIN ONLY ONLY TO TO TEST TEST VIRUS VIRUS IF IF POSSIBLE, POSSIBLE, USE USE SAME SAME BASIC BASIC PROTOCOL PROTOCOL FOR FOR TESTS TESTS AGAINST AGAINST BACTERIA, BACTERIA, VIRUSES VIRUSES & FUNGI FUNGI Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

225 MAJOR FACTORS (CONT D.) KEEP KEEP CONTACT CONTACT TIME TIME TO TO SECONDS SECONDS USE USE SOIL SOIL LOAD LOAD IN IN TEST TEST VIRAL VIRAL SUSPENSION SUSPENSION USE USE DRIED DRIED VIRAL VIRAL INOCULUM INOCULUM AS AS CHALLENGE CHALLENGE SELECT SELECT RELEVANT RELEVANT VIRUSES VIRUSES AS AS SURROGATES SURROGATES AS AS MUCH MUCH AS AS POSSIBLE, POSSIBLE, INCLUDE INCLUDE PROPER PROPER CONTROLS CONTROLS & A PREDICATE PREDICATE AGENT AGENT IN IN SAME SAME TEST TEST CONSULT CONSULT A BIOSTATISTICIAN BIOSTATISTICIAN FOR FOR MINIMAL MINIMAL NUMBERS NUMBERS OF OF PANELIST PANELIST & REPEATS REPEATS TO TO BE BE INCLUDED INCLUDED IN IN TESTING TESTING FOR FOR DECONTAMINATION OF OF HANDS HANDS AFTER AFTER TEST, TEST, USE USE A GERMICIDE GERMICIDE & PROCEDURE PROCEDURE WITH WITH KNOWN KNOWN EFFECTIVENESS EFFECTIVENESS AGAINST AGAINST THE THE TEST TEST VIRUSES VIRUSES Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

226 IN IN VITRO VITRO SUSPENSION TESTS TESTS CARRIER TESTS TESTS TYPES OF TESTS FOR TOPICALS IN IN VIVO VIVO HUMAN SUBJECTS (WHOLE HANDS, FINGERTIPS, FINGERPADS) ANIMAL MODELS EX EX VIVO VIVO HUMAN TISSUE (SKIN, (SKIN, UMBILICAL CORD, CORD, CORNEA) ANIMAL TISSUE (RAT, (RAT, GUINEA PIG) PIG) Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

227 DO VIRUSES SURVIVE ON EXPERIMENTALLY CONTAMINATED ENVIRONMENTAL SURFACES? Viruses must survive in in the the environment and and reach the the susceptible host to to initiate infection. Viruses are are discharged from infected host in in various body secretions and and excretions, which can can reach susceptible host by by direct or or indirect contact with with such contaminated surfaces particularly when infectious viral dose may may be be as as low low as as infectious units (Ijaz (Ijaz et et al., al., 1987; Sattar and and Ijaz, Ijaz, 1987, 2002; Westwood and and Sattar, 1976). Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

228 EFFECT OF ORGANIC LOAD ON THE SURVIVAL OF BVDV/HCV ON HARD SURFACES AT C AND 50 5% RH % Survival Time in Hours 10% 95% Linear (10%) Linear (95%) Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

229 SURVIVAL OF SELECTED VIRUSES ON HARD SURFACES C AND 50 5% RH % Survival Influenza Rhinovirus BVDV/HCV Linear (BVDV/HCV) Linear (Rhinovirus) Linear (Influenza) Time in Hours Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

230 SUMMARY OF HCV/BVDV RESULTS VIRUS SURVIVED > THREE DAYS AT AMBIENT RH AND TEMP. THE PRESENCE OF ORGANIC LOAD INCREASE THE VIRUS SURVIVAL. EXPERIMENT NOW BEING CONDUCTED TO STUDY THE SURVIVAL AND DISINFECTION OF BVDV SUSPENDED IN WHOLE BLOOD AS WELL USING CELL-ASSOCIATED VIRUS (SIMULATE PRESENCE OF VIRUS NATURE AND REQUIRED BY SOME INTERNATIONAL REG. AGENCIES). Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

231 DO VIRUSES SURVIVE ON HANDS? Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

232 SURVIVAL OF SELECTED VIRUSES ON FINGERPADS OF ADULTS AFTER 20 MINUTES % Survival Rhinovirus BVDV/HCV Rhinovirus BVDV/HCV Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

233 PREVENTION IS PRIMARY! Protect patients protect healthcare personnel promote quality healthcare! Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

234 IN IN VIVO TESTING OF TOPICALS Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

235 TESTING OF HYGIENIC HANDWASHING AGENTS AGAINST VIRUSES IN VIVO The The Whole-Hand Whole-Hand Method Method The The Fingertip Fingertip Method Method The The Fingerpad Fingerpad Method Method Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

236 ASTM STANDARD FOR HAND ANTISEPTICS E E METHOD METHOD FOR FOR EVALUATION EVALUATION OF OF HANDWASHING HANDWASHING FORMULATIONS FORMULATIONS FOR FOR VIRUS-ELIMINATING ACTIVITY ACTIVITY USING USING THE THE ENTIRE ENTIRE HAND HAND E E METHOD METHOD FOR FOR DETERMINING DETERMINING THE THE VIRUS-ELIMINATING EFFECTIVENESS EFFECTIVENESS OF OF LIQUID LIQUID HYGIENIC HYGIENIC HANDWASH HANDWASH AND AND HANDRUB HANDRUB AGENTS AGENTS USING USING THE THE FINGERPADS FINGERPADS OF OF ADULT ADULT VOLUNTEERS VOLUNTEERS Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

237 THE WHOLE-HAND METHOD 0.5 ml OF TEST VIRUS PLACED ONE PALM AND HANDS RUBBED & ALLOWED TO DRY FOR BASELINE, 2O ml OF ELUATE POURED ON HANDS, RUBBED AND SAMPLE COLLECTED FOR ASSAY FOR TESING HANDWASH AGENT, HAND RECEIVE ml OF PRODUCT & RUBBED FOR 10 SECOND TO MINUTES (?) WASHED IN TAP WATER, DRIED & THE VIRUS ELUTED EITHER FROM WHOLE HAND OR ONLY FINGERTIPS IN AN ELUENT ( 20.0 ml) DEPENDING ON DIFFERENT STUDIES ELUATE POST-NEUTRAIZATION ASSAYED FOR RESIDUAL INFECTIOUS VIRUS & LOG 10 REDUCTIONS DETERMINED Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004 Ijaz, Division of Biofilms, Protozoology and Virology

238 WEAKNESSES OF THE WHOLE-HAND METHOD Potentials Potentials for for virus virus wash-off wash-off during during the the pre- pre-and posttreatmentreatment tap tap water water rinse. rinse. post- Virus Virus is is spread spread over over the the entire entire surfaces surfaces of of both both hands hands only only fingertips fingertips are are sampled. sampled. The The volume volume of of recovery recovery medium medium is is too too large large (20 (20 ml) ml) concentration concentration step step needed. needed. The The volunteer volunteer can can only only be be used used to to test test either either the the control control or or only only one one of of the the product product against against a single single type type of of virus. virus. Incorporation Incorporation of of paper paper towel-drying towel-drying step step as as an an integral integral part part of of the the test test makes makes it it difficult difficult to to account account for for true true effectiveness effectiveness of of the the handwash handwash agent. agent. Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

239 WEAKNESSES OF THE WHOLE-HAND METHOD (cont d) Decontamination Decontamination of of whole whole is is difficult difficult post-experiment post-experiment due due to to large large surface surface area area and and hard-to-reach hard-to-reach interdigital interdigital and and sub-ungual sub-ungual spaces. spaces. Relatively Relatively large large volume volume (( ml) ml) of of high-titered high-titered virus virus stock stock makes makes the the method method expensive. expensive. In In spite spite of of attempts attempts to to standardize standardize hand hand washing washing procedures, procedures, there there could could be be differences differences in in techniques techniques of of hand hand washing. washing. Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

240 THE FINGERTIP METHOD Bellamy et al., (1993) 0.02 ml OF TEST VIRUS PLACED ON THE PALM SURFACE OF EACH FINGERTIPS & THUMB OF ONE HAND AND RUBBED AGAINST THE TIPS & THUMB OF THE OTHER FOR 40 S & ALLOWED TO DRY FOR 80 S THE FINGER ARE MOISTENED UNDER RUNNING TAP WATER PRIOR TO PRODUCT APPLICATION OR BASELINE RECOVERY. FOR BASELINE RECOVERY, HANDS RECEIVE 5 ml OF DI WATER & RUBBED FOR 30 SECOND, THEN RINSED FOR 15 S IN RUNNING WATER AND DRIED 15 S FOR TESING HANDWASH AGENT, HAND RECEIVE 5 ml OF PRODUCT & RUBBED FOR 30 SECOND, THEN RINSED FOR 15 S IN RUNNING WATER AND DRIED 15 S FOR VIRUS RECOVERY (BASELINE AS WELL AS POST-TEST), THE TIPS AND THUMBS ARE IMMERSED AND RUBBED FOR I MIN IN A BOWL CONTAINING 2O ml OF CELL CULTURE MEDIUM AND GLASS BEADS AND SAMPLE COLLECTED ELUATE POST-NEUTRAIZATION ASSAYED FOR RESIDUAL INFECTIOUS VIRUS & LOG 10 REDUCTIONS DETERMINED Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

241 THE FINGERTIP METHOD This This method method has has most most of of the the same same limitations limitations as as described described for for the the whole-hand whole-hand method. method. Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

242 THE FINGERPAD METHOD THE THE FINGERPAD METHOD FOR FOR VIRUCIDAL ACTIVITY IS IS AN AN ASTM ASTM STANDARD (E ). THE THE FINGERPAD METHOD FOR FOR BACTERIA IS IS ALSO ALSO AN AN ASTM ASTM STANDARD (E ). A DESCRIPTION OF OF THE THE METHOD FOLLOWS Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

243 MAIN STEPS IN IN THE FINGERPAD METHOD WITH WITH IRB IRB PERMISSION, SUBJECTS RECEIVE DETAILS ON ON STUDY & REQUESTED WRITTEN CONSENT; JUST JUST BEFORE TESTING, HANDS OF OF SUBJECT SCREENED FOR FOR ANY ANY DAMAGE TO TO SKIN; SKIN; MAIN MAIN STEPS STEPS IN IN TESTING ARE: ARE: SUBJECT SUBJECT WASHES WASHES HANDS HANDS WITH WITH UN-MEDICATED UN-MEDICATED SOAP SOAP & WATER WATER DRIES DRIES HANDS HANDS WELL WELL 3. WITH WITH PAPER PAPER TOWEL 3. HANDS HANDS RUBBED RUBBED WITH WITH TOWEL 75% 75% ETHANOL ETHANOL TILL TILL DRY DRY Dr. Sattar CREM, University of Ottawa Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

244 4. 4. THUMB- THUMB- & FINGERPADS FINGERPADS DEMARCATED DEMARCATED WITH WITH PLASTIC PLASTIC VIAL VIAL FINGERPAD METHOD (CONT D.) TEN TEN µl µl TEST TEST MICROBE MICROBE IN IN SOIL SOIL LOAD LOAD PLACED PLACED THUMBPADS THUMBPADS ELUTED ELUTED IMMEDIATELY IMMEDIATELY (INPUT (INPUT CONTROL) CONTROL THUMBPADS THUMBPADS IMMEDIATELY IMMEDIATELY DECONTAMINATED DECONTAMINATED INOCULUM INOCULUM ON ON FINGERPADS FINGERPADS ALLOWED ALLOWED TO TO DRY DRY WHEN WHEN INOCULUM INOCULUM DRIES, DRIES, TWO TWO FINGERPADS FINGERPADS ELUTED ELUTED (BASELINE (BASELINE Dr. Sattar CREM, University of Ottawa Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

245 FINGERPAD FINGERPAD TREATED TREATED WITH WITH 1 1 ml ml OF OF TEST TEST SUBSTANCE SUBSTANCE OR OR CONTROL CONTROL SOLUTION SOLUTION FINGERPAD METHOD (CONT D.) FINGERPAD FINGERPAD ELUTED ELUTED WITH WITH 1 1 ml ml OF OF ELUENT ELUENT WITH WITH OR OR WITHOUT WITHOUT WATER WATER RINSE RINSE OR OR DRYING DRYING SKIN SKIN SURFACE SURFACE SCRAPED SCRAPED ON ON INSIDE INSIDE LIP LIP OF OF VIAL VIAL TO TO RECOVER RECOVER MOST MOST OF OF ELUATE ELUATE FINGERPADS FINGERPADS DECONTAMINATED DECONTAMINATED HANDS HANDS WASHED WASHED WITH WITH SOAP SOAP & WATER WATER HANDS HANDS DRIED DRIED WELL WELL WITH WITH PAPER PAPER TOWEL TOWEL Dr. Sattar CREM, University of Ottawa Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

246 ADVANTAGES OF OF THE FINGERPAD METHOD MEASURED MEASURED VOLUME VOLUME OF OF TEST TEST INOCULUM INOCULUM PLACED PLACED ON ON A WELL WELL DEFINED DEFINED AREA AREA & DRIED DRIED DRIED DRIED INOCULUM INOCULUM EXPOSED EXPOSED TO TO A KNOWN KNOWN VOLUME VOLUME OF OF TEST TEST FORMULATION FORMULATION FOR FOR A DEFINED DEFINED & SHORT SHORT CONTACT CONTACT TIME TIME INFECTIOUS INFECTIOUS AGENT AGENT STAYS STAYS WHERE WHERE IT IT WAS WAS PLACED PLACED CONTROL CONTROL & REFERENCE REFERENCE SOLUTION SOLUTION CAN CAN BE BE INCLUDED INCLUDED IN IN THE THE SAME SAME TEST TEST ALONG ALONG TEST TEST FORMULATION FORMULATION Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

247 ADVANTAGES (CONT D.) CAN DISTINGUISH BETWEEN PATHOGEN LOSS DUE TO MECHANICAL REMOVAL, IN SITU INACTIVATION & POST-TREATMENT WATER RINSING & TOWEL OR AIR-DRYING CAN BE USED WITH CONVENTIONAL OR HANDRUB FORMULATIONS SUITABLE FOR WORK WITH ALL MAJOR CLASSES OF MICROORGANISMS GIVES RESULTS COMPARABLE TO THOSE WITH THE WHOLE-HAND METHOD Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

248 ADVANTAGES (CONT D.) THE FINGERPAD METHOD HAS BEEN USED FOR EVALUATION OF VARIETY OF HAND WASH AGENTS BY A NUMBER OF DIFFERENT LABS HERE IN NORTH AMERICA INCLUDING EUROPE. Woolwine and Gerberding (1995) Steinmann et al., (1995) Mbithi et al., (1993) At MICROBIOTEST, WE HAVE TESTED AN ALCOHOL-BASED PRODUCT AGAINST RHINOVIRUS AND BVDV/HCV Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

249 ALCOHOL-BASED ANTISEPTICS MAJOR MAJOR RELEVANCE RELEVANCE IN IN HAND HAND ANTISEPSIS ANTISEPSIS INCREASING INCREASING ACCEPTANCE ACCEPTANCE EVEN EVEN IN IN U.S. U.S. & CANADA CANADA CONVENIENT, CONVENIENT, SAFE, SAFE, FAST-ACTING FAST-ACTING & ENVIRONMENTALLY-FRIENDLY FOR FOR USE USE BETWEEN BETWEEN HANDWASHINGS HANDWASHINGS FORMULATIONS FORMULATIONS WITH WITH >60% >60% ALCOHOL ALCOHOL BROAD-SPECTRUM GERMICIDES, GERMICIDES, INCLUDING INCLUDING ACTIVITY ACTIVITY AGAINST AGAINST MANY MANY NON-ENVELOPED NON-ENVELOPED VIRUSES VIRUSES HEPATITIS HEPATITIS A, A, CALICI- CALICI- & PARVOVIRUSES PARVOVIRUSES MAY MAY BE BE RESISTANT RESISTANT SOME SOME CONCERNS CONCERNS WITH WITH AIR AIR QUALITY QUALITY Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

250 THE EFFECTIVENESS OF AN ALCOHAL-BASED HAND GEL AGAINST RHINOVIRUS AND BOVINE VIRAL DIARRHEA VIRUS (SURROGATE FOR HEPATITIS C VIRUS) VIRUS TESTED REDUCTION VIRUS TITER IN VITRO BASELINE CONTROL TEST PRODUCT REDUCTION VIRUS TITER WITH TEST PRODUCT P VALUE Bovine viral diarrhea virus <0.001 Rhinovirus Type < FOR RHINOVIRUS 12 & FOR BVDV 6 SUBJECTS WERE USED. 10 ul OF EACH VIRAL INOCULA WAS PLACED ON EACH DIGIT & DRIED. EXPOSED TO 1 ml OF THE PRODUCT FOR 15 S. POST-EXPOSURE, ELUATE WERE ASSAYED FOR RESIDUAL INFECTIOUS VIRUS AND LOG 10 REDUCTION WAS CALCULATED. Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

251 TESING ANTI-VIRAL ACTIVITY OF HAND ANTISEPTICS: POTENTIAL SURROGATE VIRUSES VIRUSES ASSAY SKIN SAFETY SURVIVAL ======================================================================= Adenovirus Yes Yes Good Bovine viral diarrhea virus/hcv Yes Yes Good Feline calicivirus/norwalk Yes Yes Good Hepatitis A virus Yes Yes Very Good Rhinovirus Yes Yes Good Rotavirus Yes Yes Very Good Respiratory syncytial virus Yes Yes Very Poor ======================================================================== Ansari & Sattar, 2003; Ijaz et al., unpublished data Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

252 ISSUES TO BE RESOLVED IS IS IN IN SITU SITU PATHOGEN INACTIVATION NECESSARY? SHOULD WE WE ACCOUNT FOR FOR PATHOGEN REMOVAL WITH WITH POST- POST- TREATMENT RINSE RINSE & DRYING? WHAT WHAT SHOULD BE BE THE THE PERFORMANCE CRITERIA FOR FOR HANDWASH & HAND HAND RUBS? WOULD SURROGATES BE BE ACCEPTABLE? IS IS RESIDUAL ANTI-VIRAL ACTIVITY NEEDED? HARMONIZATION OF OF TEST TEST METHODS FDA FDA MONOGRAPH? CTFA/SDA CITIZEN S PETITION TO TO FDA FDA ON ON VIRUCIDAL ACTIVITY OF OF HAND HAND ANTISPETICS MICROBIOTEST s PROTOCOL TO TO TO TO FDA FDA ON ON VIRUCIDAL ACTIVITY OF OF HAND HAND ANTISPETICS Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

253 CONCLUSIONS EMERGING AND RE-EMERGING VIRAL INFECTIONS RESULTS FROM THE MULTIFACTORIAL INTERACTION OF HUMANS WITH THEIR ECOSYSTEM. ENTERIC, HEPATITIS & RESPIRATORY VIRUSES STUDIESD SURVIVE IN THE ENVIRNMENT AS WELL AS ON HANDS WHICH COULD ENABLE THEIR SPREAD TO THE HOST. HAND ANTISEPTIC AGENTS PLAY AN IMPORTANT ROLE IN INTERRUPTION OF VIRAL DISSEMINATION FROM SURAFCE-TO- HAND-TO-HAND AND FINGERTIPS TO MOUTH FROM THE ENVIRONMENT TO HUMAN POPULATIONS. GLP VIRUCIDAL METHODS FOR TESTING EFFICACY OF HAND ANTISEPTIC AGENTS ARE AVAILABLE. DATA GENERATED BY FINGERPAD METHOD HERE IN NORTH AMERICA AND EUROPE CONFIRMED THE VIRUCIDAL DATA GENERATED BY THE WHOLE-HAND METHOD. SURVIVAL AND DISINFECTION STUDIES OF VIRUSES IN BLOOD AND CELL- ASSOCIATED VIRUSES UNDERWAY. Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004

254 Ijaz, MK, HAND ANTISEPTICS NEED FOR TESTING & LABEL CLAIMS AGAINST VIRUSES, ASTM-Washington, DC, October 2004