1 April 15, 2005 ADDITIONAL COMMENTS CONCERNING SEPARATE SHIPMENT OF AFTERTREATMENT SYSTEMS FOR HIGHWAY APPLICATIONS 85.1713 Delegated assembly exemption 1. Section 85.1713( b)( 6) requires that the engine manufacturer " keep records to document how many engines you produce under this exemption." A record of engine quantities built under the exemption seems a rather useless record for either the manufacturer or for EPA. This requirement should simply be stated as a requirement to keep affidavits on file for the 5 year duration specified.

2. Section 85.1713 ( e) states that the exemption expires when the OEM " takes possession" of the engine. This could be problematic in that if, for some reason, the engine must be returned to the engine manufacturer, the expired exemption will have prohibited its shipment back the engine manufacturer's facility. EMA proposes that the language be modified to state that " Once the vehicle manufacturer installs the engine into the vehicle with the required aftertreatment, the exemption expires "

3. Section 85.1713 ( g)( 1) states that " If we suspend or revoke the exemption for any of your engine families under this paragraph ( g), this exemption will not apply for future certificates unless you demonstrate that the factors causing the nonconformity do not apply to the other engine families." While we believe we understand the intent, it implies that there is no opportunity for an engine manufacturer to take corrective action so as to restore the exemption in future model years for the engine family for which the exemption was revoked, and likewise have it available for other engine families for which similar circumstances might exist, even if the corrective action can be applied to those families as well. EMA requests that EPA add language to provide for the opportunity that the engine manufacturer can restore its good standing with EPA and take advantage of the exemption where needed.

4. Section 85.1713 ( c)( 3)( v) allows for engine manufacturers who also produce vehicles to " meet your auditing responsibilities under paragraph ( c)( 2)( iii) of this section by maintaining a database showing how you pair aftertreatment components with the appropriate engines." The reference to " paragraph ( c)( 2)( iii)" should be " paragraph ( c)( 3)( iii)."

5. Section 85.1713 ( c )( 3)( vi) requires that manufacturers keep records of audits, but it is unclear whether they should likewise be maintained for 5 years as is the case for contractual agreements as specified in 85.1713 Section ( b)( 6). Two North LaSalle Street Suite 2200 Chicago, Illinois 60602 Tel: 312/ 827 8700 Fax: 312/ 827 8737 www. enginemanufacturers. org 2 6. Section 85.1713 ( f) requires the engine manufacturer to " notify us within 15 days if you find from an audit or another source that a vehicle manufacturer has failed to meet its obligations under this section." This requirement is in conflict with Section 85.1713 ( c)( 3)( vi), which states that the engine manufacturer " must keep records of these audits and provide a report describing any uninstalled or improperly installed aftertreatment components to us within 90 days of the audit." EMA proposes that the conflicting language of Section 85.1713 ( f) be deleted, and that Section 85.1713 ( c )( 3)( vi) ( 90 days) be retained as the required timing for submission of such a report.

EMADOCS: 6708.2


Panel Members:
Matthew J. Arduino, M.S., Dr.P.H., FSHEA, RM(NRCM), M(ASCP)cm
Chief, Clinical and Environmental Microbiology Branch
Centers for Disease Control and Prevention

Joel Bozue, Ph.D.
Bacteriology Division
USAMRIID

Christina Egan, Ph.D.
Chief, Biodefense Laboratory, Wadsworth Center
New York State Department of Health

Lynne M. Sehulster, Ph.D., M (ACSP)
Prevention and Response Branch, Division of Healthcare Quality Promotion
Centers for Disease Control and Prevention

 Suitability of the Protocol:  The protocol has been revised to include additional methodology for preparing the test microbe, chemical and physical abrasion, details on materials and supplies, and quality control practices. Refer to Appendix A for an overview of the protocol changes. Please comment on the following issues:
 Do the revisions summarized in Appendix A provide a substantial improvement and technically sound approach for testing the antimicrobial properties and product durability of solid copper/copper alloy materials?  If not, please provide advice on any additional elements that should be addressed or modified.
         Arduino: The approach appears to be sound.  However, unlike other disinfectant and sanitizers resistance does occur to some extent and a number of copper resistance genes have been identified (eg., copB, copC, copY, cueO, tcrA, tcrB, tcrZ, etc).  Should a cooper resistant/tolerant strain be included in the efficacy testing?
         What do we know about neutralizing capacity of the recovery medium Cu[2+] so that any potential carry-over of copper into the culture media would not interfere with recovery of the test organisms.  Microbiologic methods from the enclosed studies are relatively lacking sufficient detail to ensure.  The references by Schmidt cite an early study (again lacks detail but looks like lecithin was used as a neutralizer).  Should recovery media include a known metal chelating agent (EDA, DETA, EDTA, thioglycollate or other known chelating agent).  Currently published studies do not appear to use a chelating agent.
         Should we incorporate thioglycollate (see:  Landeen LK, Yahya MT, Gerba CP.  Efficacy of copper and silver ions and reduced levels of free chlorine in inactivation of Legionella pneumophila. ApplEnvironMicrobiol 1989;55(12):3045-3050 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC203221/)

         Bozue: It is difficult to say if there is an improvement to this revision as the reviewer was not involved in an initial protocol review.  Overall, this protocol should be suitable once additional questions, details, and some potential challenges to the submitters are provided/ clarified.  Details for concerns/ questions are listed below in response to specific questions.  However, in researching this topic, it was a bit disconcerting that a recent published review (Journal of Hospital Infection 92 (2016) 7-13) on the topic of antimicrobial surfaces in healthcare facilities has called into question the results of one the publications (Salgado, 2013) provided for this review.  Some of the data within Salgado, 2013 was referred to as "implausible" and states there is "considerable uncertainty" on the ability of copper to reduce/ prevent infections.  Though, this does not rule out the ability of copper to reduce bacterial CFU numbers.
         Egan: The protocol and most of the revisions to the original protocol are technically sound and provide a sound approach for this study. I think the removal of E. aerogenes from the testing protocol is acceptable as it is not essential to include because both P. aeruginosa and S. aureus are in the study. I do not think that substantial information will be lost by not including E. aerogenes. Testing of the other 2 organisms to cover both gram positive and gram negative non-spore forming bacteria will provide sufficient microbial activity. An additional element that should be addressed in the lack of any testing utilizing spore forming organisms. There will be no data generated that will test the copper/copper alloy surfaces using spore forming organisms such as Clostridium difficile. It would be highly advantageous to include in the testing protocol, a bacterial spore former. This is a highly important type of bacteria- especially when dealing with health-care facilities that have large numbers of infections due to these organisms.
         In addition, it is not clear why the 12 week period to 8 weeks period was revised as there was no support guidance provided to show that this time reduction is acceptable. There should be some supporting data to justify the reduction.
         Sehulster: The modifications as outlined in Appendix A seem reasonable and provide some needed clarifications.  I have a question about the preparation of the carriers.  In the protocol it is stated that flaming, autoclaving, or using UV light is not recommended for carrier sterilization because of possible adverse effects on the carriers.  Has the use of a dry heat oven been ruled out at well?  I'm concerned that simple immersion in alcohol for a short period of time may not be a satisfactory alternative to a physical method of sterilization.

 Is the protocol of sufficient detail so that it may be conducted by a qualified testing laboratory and is likely to result in reproducible results when conducted in different testing facilities and/or at different times within the same laboratory?  If the protocol is not of sufficient detail, which areas require improvement?

            Arduino: So if MB-25 is used with TSB as the growth medium do we know whether some small amount of copper that may end up in solution is not inhibitory to the test organisms leading to false results.  Should thioglycollate be included be incorporated?  Need to include a more detailed section regarding neutralization and give some examples of materials to be used in the neutralization of Cu[2+].

            Bozue: Enough detail is provided in the protocol for qualified personnel to perform the procedures.  However, the changes listed to Appendix A state that Enterobacter will not be tested, but the protocol still has it included.

            Egan: The protocol was well written and clear and a qualified laboratory/laboratorian will be able to perform it with the protocol as written. There are only 2 areas of potential weakness- one is in the test culture method- variability in the stock culture could lead to variable numbers of organisms if a particular starting concentration is not specified. The other area is in any PPE that the laboratorians would need to utilize for the study. This should be specified in the protocol. For example, are gloves required? For sterility testing and using sterile coupons, any potential sources of contamination should be minimized thus gloves and a lab coat should be worn while performing these studies and should be specified in the protocol.

            Sehulster: Knowing the meticulous approach EPA uses for method development, I'm assuming the agency has conducted the intra-laboratory and inter-laboratory validation testing for the method.  If they have completed this phase of development, then I would be confident that the method can be performed reliably in a responsible testing laboratory.  There is one aspect of the protocol that concerns me, and that is the allowance of what could be a great deal of variability in materials, especially for the carrier materials.  The protocol indicates that descriptions must be entered into the results record, but does the agency have confidence that the reported culture results are accurate and valid, given the potential variability?  It would seem to me that the agency should specify the carrier materials so that all the labs would be using the same materials, thereby eliminating one major variable in the analysis of the results.

 Is the protocol suitable for evaluating the antimicrobial efficacy of solid copper/copper alloy materials, as well as copper-impregnated or coated surface materials?   If the protocol is not suitable for one or both, please provide advice on how to modify the protocol to cover both materials.

            Arduino: Yes, once neutralization or chelation of residual Cu[2+] is addressed in sufficient detail to allow a standardized approach for different laboratories to use.

            Copper tolerance and resistance does occur in nature among strains representing several genera of both gram-negative and positive bacteria (see 3b). Including some strains of MRSA (see below Emergence of copper resistant MRSA in Irish hospitals).  This is especially true among strains among food animals (cows and pigs).  It's theoretically possible that some of these strains could colonize humans.

            Kinnevey PM, Shore AC, Brennan Gi, Sullivan DJ, Ehricht R, Monecke S, Slickers F, Coleman DC.  Emergence of sequence type 779 methicillin resistant Staphylococcus aureus harboring a novel pseudo staphylococcal cassette chromosome mec (SCCmec)-SSC-SCCCRISPR composite element in Irish hospitals.  Antimicrobial Agents Chemother 2013;57(1):524-531 (Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535981)

            Bozue: I believe this protocol could be applied to testing the antimicrobial activity of other copper containing materials once considering the reviewer's suggestions and critiques as detailed throughout this review.

            Egan: Yes, the protocol is suitable for both solid copper as well as copper-impregnated and coated surface materials.

            Sehulster: In my opinion, I would separate the testing of spray-on copper products from the copper-clad materials.  Statement #10 (under A. Carriers) is the statement of asking the lab to provide the agency with the details about the surfaces used for the spray-on product testing.  I see too much potential variation here.  In my opinion, I would suggest that the agency specify three or four standard materials (e.g., stainless steel, plastic, glass, a painted surface, etc.) and direct the labs to spray the copper product onto these standard materials as carriers and proceed with testing, including the necessary controls.  In addition, I would think that the agency would want to know how durable the antimicrobial properties are for spray-on products.  Can the product be "recharged" in some fashion, or must the product be re-applied?

One question  -  how does use of a spray-on copper product relate to EPA's Treated Article Exemption?  The whole purpose of a spray-on product under these circumstances would be to apply an antimicrobial residual to a surface in efforts to reduce microbial pathogen spread to and transfer from hard surfaces.  Is a sprayed surface to be tested for antimicrobial efficacy in a laboratory adequate to meet the criteria in this part of FIFRA?

 There is an interest in using the protocol to evaluate other types of hard non-porous surfaces impregnated with antimicrobial agents other than copper (other solid metals, metal alloys, fabricated materials etc.).  Is the protocol suitable for testing the antimicrobial activity of other types of hard, non-porous surfaces treated or impregnated with antimicrobial agents?  If not, please explain why and offer advice on how to change the protocol so that it would produce reliable, reproducible results when testing these other surface types.

            Arduino: The general protocol could serve as template for other surfaces.  The carriers for controls however, may not necessarily be stainless steel.  They may reflect the base (non-impregnated material).

            As for nonporous surfaces, until and agreed upon standardized method is available to test the efficacy of disinfectants against nonporous surfaces this is probably not ready to move forward as of yet.

            Is it possible to use a modified version of the AATCC TM 100 Antibacterial textile testing for some of the porous materials (American Association of Textile Chemists and Colorists)?  This may require broader discussion.

            Even for EPA registered disinfectants there are no products registered for porous materials.  There are registered carpet and upholstery cleaners.

            Bozue: I believe this protocol could be applied to testing antimicrobial activity of other substances once considering the reviewer's suggestions and critiques as detailed throughout this review.

            Egan: I think the approach would work for most other metals and metal alloys for hard non-porous surface testing. I think additional analysis may have to be performed with some fabricated materials that may not be a consistent in texture i.e. may have a coating or structure that is not a similar smooth surface that may not be suitable for sampling in the manner outlined in the protocol. This may not be an issue but should be considered.

            Sehulster: By saying "there is interest..." it's evident that the agency has not moved in this direction as yet.  The current protocol could be used to start the validation process, but as it stands now  -  no  -  there's a great deal more work to be done.  All the details of the experimental methods would need to undergo validation, complete with intra-lab and inter-lab testing.  It is possible that the method might need to be adjusted or revised as a result of the validation process.  Detailed descriptions of materials, experimental conditions (e.g., temperature, relative humidity, etc.), recommended suppliers of carrier materials, etc. would need to be included.  The challenge bacteria would have to be evaluated to determine if they are suitable.

 Controls:  Stainless steel was selected as the control carrier material due to the inert nature of the material.  The final log reduction values are calculated by taking the log 10 difference between the stainless steel control carriers and the product test carriers.
 In the protocol, the stainless steel control carriers are not subjected to the mechanical surface abrasion or the chemical treatments (A, B, and C). Please comment on the suitability of this approach.  If this approach is not appropriate, please provide advice on how to address the management of the control carriers.

            Arduino: The untreated stainless steel coupons provide a baseline control of organisms deposited onto an untreated surface.

            One should remember that different surface materials have different characteristics that can influence drying, persistence, and survival.  Some surface characteristics also impact bacterial recovery (eg. ability to remove some organisms from the surfaces) when other parameters are equivalent (temp, RH, matrices, etc).  This is true of most persistence studies (see studies on Ebola, Yersinia pestis, and others.

            Cook BW, Cutts TA, Nikiforuk AM, Poliquin PG, Court DA, Strong JE, Theriault SS.  Evaluating environmental persistence and disinfection of the Ebola virus Makona variant. Viruses 201514;7(4):1975-86. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411685/)

            Rose LJ, Donlan R, Banerjee SN, Arduino MJ.  Survival of Yersinia pestis on environmental surfaces.  Appl Environ Microbiol  2003;69(4):2166-2171 (http://www.ncbi.nlm.nih.gov/pmc/article/PMC154802)

            Sagripanti JL, Rom AM, Holland LE.  Persistence in darkness of virulent alphaviruses, Ebola virus, and Lassa virus deposited on solid surfaces.   Arch Virol. 2010;155(12):2035-9 (http://link.springer.com/article/10.1007%2Fs00705-010-0791-0).

            Bozue: It is not clear to this reviewer as to why the stainless steel control carriers are not subjected to the same the mechanical surface abrasion and chemical treatment as the copper carriers.  For these to serve as an appropriate control, they should be treated the same as the test ones.  Is there a specific rationale for the submitters not to include these treatments with the control strains, cost or to save time in the processing  of the samples, as the protocol allows the steel coupons to be reused and the abrasion/ chemical treatments are 3x a day/ 5 days a week/ for 12 weeks?

            Egan: The control carriers should be subjected to both treatments, or at minimum have another set of controls that are subjected to both treatments in order to have an accurate comparison of the results. Ideally, the results should then be compared to the control carriers that have been subjected to the surface abrasion and chemical treatments.

            Sehulster: In my opinion, you should limit the differences between controls and test carriers as much as possible, leaving that which is to be tested the only difference.  I think it would be important to include control carriers that have been subjected to the abrasion and chemical treatments.

 Please comment on whether the comparative analyses of log reduction values (i.e., the difference in the level of microbes on exposed carriers vs. unexposed carriers and stainless steel control carriers) is a technically sound approach to the assessment of the antimicrobial activity of the copper and copper alloy products.

            Arduino: One might also consider comparing surface abraded and chemically treated control stainless steel carriers to see how these compare to the exposed carriers.  While the Stainless steel control carriers base ideal (smooth surface, clean surface), a set of abraded, chemically treated carriers might represent an additional test comparable challenge to the exposed carriers.  This assumes that exposed carriers (physical and chemically treated) may provide areas where microbes would be harder to remove, or offer areas of protection when combined with soil.

            Bozue: It would be helpful to the reviewer to better assess these possibilities if the submitter provided some examples of results from performed studies to judge the retention of bacteria to the various coupons.  Assuming that "a fair amount" of bacteria are still adhering to the inert stainless steel coupons from what was added; this reviewer would feel comfortable in comparing between these two variables.

            Egan: Overall, the protocol was very well written however, the calculations/data analysis was somewhat confusing. I think that there should be some additional information included on determining the plate counts. There may be some control carriers that are too numerous to count and should not be used for the determination. I think that the comparison of the number of organisms compared from exposed carriers to unexposed carriers and stainless steel controls is acceptable.

            Sehulster: In my opinion, I think the agency should continue to use the analyses of log reduction values as the description of the efficacy of the product.  This will help the manufacturers market their product to the customers  -  healthcare facilities.  The infection prevention nurses and environmental services directors/supervisors are familiar with this expression of potency and will be looking for this information on the product literature and basing their decision on this property (not to mention the cost).

 Contact Time:  EPA's current guidance requires that a hospital disinfectant kill between five to six logs (100,000 to 1,000,000) of the target microbe in a qualitative test system within the time frame specified on the product labeling.  The use of copper and copper alloy products in medical care facilities is a supplement to (not a replacement for) standard infection control practices and use of EPA registered hospital disinfectants.
 In a standard chemical disinfectant test, the microbe is applied to the carrier surface, allowed to dry, and then exposed to the disinfectant.  The contact time for the chemical disinfectant begins upon application of the disinfectant.  For copper and copper alloy materials, the surface serves as the antimicrobial agent.  The protocol specifies that the contact time begin upon application of the microbe to the surface, not after the microbe has dried on the surface.  Please comment on whether it is appropriate for the contact time to begin upon inoculation of the surface, and if not, please offer alternative approaches for this step in the protocol.

            Arduino: The theory behind the copper impregnated surfaces is the the activity begins on contact with the surface.  So the activity begins at inoculation.  The current protocol accounts for this the initiation of contact time (CT) begins upon inoculation of the carrier and then the carrier is allowed to sit for 1 hr (EPA.  Protocol for the evaluation of bactericidal activity of Hard, non-porous copper/copper-alloy surfaces, rev 02/03/15) and is adequate.

            Similar studies are performed when evaluating the disinfection of pathogens in water, where the measurement of CT starts at the onset of inoculation.

            Bozue: If the surface is the "disinfectant", it would be "fair" for the contact time to begin at the inoculation.  If anything, additional CFU killing would occur if the time was extended to wait for the inoculum to dry.

            Egan: I think it is appropriate for the contact time to begin upon application of the bacterial organisms to the surface. If the bacterial inoculation is allowed to dry and then the contact time is started, there would actually be a longer than 1 hour contact time which would not be accurate.

            Sehulster: In my opinion, the answer to this question is yes.  From my perspective, the whole rationale for having copper-clad items is/was to continually inactivate microorganisms, albeit on a lower level compared to a disinfectant, but the use of these surfaces does not eliminated the requirement that healthcare facilities continue with their routine surface disinfection.  With regards to starting the clock with the application of the challenge bacteria as opposed to allowing the inoculum to dry, this approach mimics a real situation.  Bacteria in droplets, moisture from the hands, etc. would be most likely to make initial contact with these and other surfaces.

 Please comment on whether a single inoculation per carrier (4-5 logs bacteria per carrier) for both Staphylococcus aureus and Pseudomonas aeruginosa provides adequate challenge to evaluate the level of antimicrobial activity.  A soil load (three-part) is also added to the inoculum before carrier inoculation.  If a single inoculation is not appropriate, explain why and provide suggestions on how to improve the inoculation procedure.

            Arduino: A single inoculum per carrier should be sufficient as long as data from replicates are consistent.  By using 4-5 logs of test organisms one should be able to note a 3 log reduction.  If wanting to measure more than 3 logs one might use a single inoculum containing > 10[5]-10[6] CFU.

            There are organisms that exhibit heavy metal resistance/tolerance and in some of these are copper resistant or tolerant (eg. Strains of Cronobacter sakazakii, Cupriavidus, Enterococcus faecalis, Escherichia coli, Ralstonia, Salmonella etc.)  I've highlighted a few references:

            Brown NL, Rouch DA, Lee BT. Copper resistance determinants in bacteria.  Plasmids 1992;27(1):41-51.

            Cervantes C, Gutierrez-Corona F. Copper resistance mechanisms in bacteria and fungi.  FEMS Microbiol Rev 1994;14(2):121-137

            Dupont CL, Grass G, Rensing C.  Copper toxicity and the origin of bacterial resistance -- new insights and applications.  Metallomics 2011;3(11):1109-18.

            Silveira E, Freitas AR, Antunes P, Barros M, Campos J, Coque TM, Peixe L, Novais C.  Co-transfer of resistance to high concentrations of copper and first-line antibiotics among Enterococcus from different origins (humans, animals, the environment and foods) and clonal lineages. J Antimicrob Chemother 2014;69(4):899-906. (available from http://jac.oxfordjournals.org/content/69/4/899.long)

            Bozue: It is the opinion of a reviewer that a single inoculating dose would be adequate for a challenge dose.  However, it would be tempting to enhance the dose to determine the potential for the copper surfaces to prevent the ability of biofilm formation or killing the inoculation of a biofilm added to these surfaces in addition to a single dose.  Many bacteria survive in the environment and on/ in humans as biofilms, especially the test bacteria to be used in these studies, P. aeruginosa and S. aureus.  This may be above and beyond the scope of the claim of these products, but the presence of bacterial pathogens as biofilms would be extremely relevant in healthcare facilities.  Many of the surfaces components (shower heads, fountains, whirlpools, etc.) listed in the literature provided would certainly contain biofilms.   Also, have the submitters tested or considered the ability of the copper surfaces to be microbicidal against spore forming bacteria, such as Clostridium difficile due to the threat it poses in healthcare settings?  If it is, it certainly would be a bonus for labelling purposes.

            Egan: I think that this single inoculation concentration provides an adequate challenge to evaluate the level of antimicrobial activity for this type of application. Multiple inoculations would be introducing another variable that could affect study results. By including the soil load, I think that the study will provide an adequate analysis of expected bacteria and environmental material that would be more than what would be expected on a routine surface.

            Sehulster: This is an interesting question, given it's been the agency's standard protocol to use the separate challenge approach (I.e., one genus/strain of bacteria as the challenge for each experiment).  While a mixed culture might be closer to the reality of what's on a hard surface in a real life setting, this still represents a major departure from agency protocol.  In addition, the vast majority of researchers use pure cultures for their experiments, not mixed cultures.  If you were to incorporate a mixed culture as the challenge inoculum, you would have to repeat basically all of the validation experiments to ensure that this does not generate problems that would interfere with the analyses and interpretation of the results.  What is your confidence level regarding the preparation of the mixed culture?  Would you use equal concentrations of each bacteria or more of one and less of the other?  Going with a mixed culture means another round of validation studies.

 Based on the Agency's experience in utilizing hard non-porous carriers in standard efficacy test methods, microbial populations on environmental surfaces decline naturally over time mainly due to desiccation.  This natural decline presents challenges in determining whether the decline in a microbial population is due to desiccation or antimicrobial activity. An antimicrobial surface such as copper should be capable of accelerating the decrease in the number of surface-associated bacteria.  The Agency expects that an antimicrobial effect due to the product should be measureable within a one hour timeframe. The original protocol specified a 99.9% reduction of viable bacteria within two hours of inoculation while the new protocol specifies a one hour timeframe.   Please comment on the suitability of reducing the timeframe from two hours to one hour, or if the specified timeframe is not reasonable, provide advice on a suitable timeframe.

            Including the use of the untreated controls may assist (stainless steel) in determining the loss upon drying and there actually may be no way to actually account for this loss.

            However, one must realize that survival on surfaces is a complex and involves suspending media (matrices), surface characteristics, organism factors, temperature and relative humidity.   Depending on the test organisms being used loss with in an hour may be minimal (in many of our ongoing studies of healthcare associated pathogens) > 3 log reduction has been seen after 24 hrs with the exception of Acinetobacter baumannii and the gram positive organisms (eg enterococci, staphylococci, and bacterial endospores).  We do know that Y. pestis has a more rapid decline.

            See:  Esteves DC, et al.  Influence of biological fluids in bacterial viability on different hospital surfaces and fomites.  Am J Infect Control 2015 Nov 12 (ahead of print)

            Kramer A, Schwebke I, Kampf G.  How long do nosocomial pathogens persist on inanimate surfaces?  A systematice review.  BMC Infect Dis 2006; 6:130 (available from http://www.ncbi.nlm.nih.gov/pmc/article/PMC1564025)

            Rose LJ, Donlan R, Banerjee SN, Arduino MJ.  Survival of Yersinia pestis on environmental surfaces.  Appl Environ Microbiol  2003;69(4):2166-2171 (http://www.ncbi.nlm.nih.gov/pmc/article/PMC154802)

            Shams AM, Rose LJ, Hodges L, Arduino MJ.  Survival of Burkholderia pseudomallei on environmental surfaces.  Appl Environ Microbiol 2007;73(24): 8001-4 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2168135)

            Zarpellon MN, et al. Survival of vancomycin-intermediate Staphylococcus aureus on hospital surfaces.  J Hosp Infect 2015;90(4):347-5.

            Bozue: The reviewer agrees that bacteria would naturally decline overtime and have noted this is in my laboratory work.  However, this would not be an issue for this protocol if the # of CFU deposited initially would be known for both the copper containing versus the non-copper control coupons.   In Appendix A/Section IV/B/5, it is stated that determining the titer of the final test culture be "recommended".  When considering the natural decline, determining the titer should be "required".  Knowing the total CFU titer would then allow determining natural decline versus killing due to the presence of the copper.

            Egan: The 1 hour timeframe is suitable and reasonable for this protocol. These studies could be recommended to be performed in a dead-air box rather than a biosafety cabinet- which has laminar air flow that will accelerate the desiccation.

            Sehulster: Going with a one-hour contact time as opposed to a two-hour contact time signifies to me that the agency is expected a greater, more efficient antimicrobial effect with the current copper products.  I'm assuming the manufacturer of the copper has published evidence that the product achieves several log reductions in as little as one hour.  Experiments depicting inactivation over time elapsed will confirm this.  I don't envision a problem with setting the contact time at one hour.  In real life uses, however, the antimicrobial activity of copper is expected to be continual, so at any given time there will be numbers of inactivated microorganisms on a surface and numbers of live, freshly deposited microorganisms that will soon become inactivated.

 Please comment on whether copper and copper alloy products that kill 99.9% of target microbes within 1 hour would provide a significant benefit in reducing levels of target microbes in medical care facilities.  If you think that killing 99.9% of target microbes within 1 hour would not provide a significant benefit in reducing levels of target microbes in medical care facilities, please offer advice on the level of antimicrobial activity that would provide such benefits.  Please explain the basis for your conclusions.

            Arduino: Health outcomes data regarding the use of antimicrobial impregnated surfaces that products is still lacking.  Though there are published studies that claim that the use of these copper impregnated surfaces yield reductions in healthcare-associated infections have been published.  However, a recent review (Muller et al, 2016) finds the data quality of these studies to be quite low.

            More evidence is needed to show a link with log reduction on surfaces and prevention of HAIs.  So unknown whether a log reduction would have an effect, though it may predict the ability to recover certain HAI pathogens, eg., multiply drug resistant ornganisms from the patient care environment.

            From some of our studies of these "noncritical" surfaces" in patient rooms after routine and terminal cleaning is that contamination is quite broad (2014 IDSA Poster attached).

            Shams A, Rose LJ, Edwards JR McDonald LC, Arduino MJ, Noble-Wang J.  Assessment of the overall and multi-drug resistant organism bioburden on environmental surfaces in healthcare facilities.  Open Forum Infect Dis 2014; 1(Suppl 1):S358,  (http://ofid.oxfordjournals.org.content/1/suppl_1)

            McDonald LC, Arduino 1 MJ.  Editorial commentary: climbing the evidentiary hierarchy for environmental infection control.  Clin Infect Dis 2013;56(1):36-9 (http://cid.oxfordjournals.org/content/56/1/36.long)

            Muller MP, MacDougall C, Lim C, Ontario Agency for Health Protection, PIDAC-IPC. Antimicrobial surfaces to prevent healthcare-associated infections:  a systematic review.  J Hosp Infect 2016;92:7-13.

            Environmental Hygiene in Healthcare Research (September 2015) http://www.cdc.gov/hai/research/eic-meeting.html

            Bozue: If the copper products were able to decrease pathogenic microbes by 99.9% within one hour of contact time in a medical care facility, this should provide a significant benefit in the potential to curb hospital acquired infections, especially to a population that would be at a greater susceptibility to organisms that may only be of a slight risk to a "normal healthy" population.  The potential to lower this risk would be an ethical/ moral benefit in addition to an economic benefit where the hospital stay of these individuals would be not be overly extended due to a unnecessary nosocomial infections.

            Egan: Yes, I think that being able to kill 99.9% of target microbes within one hour would be of significant interest and benefit health care facilities. In combination with routine cleaning that is performed with EPA approved disinfectants, it would provide an additional safeguard and control that will assist in infection control and reduction in hospital acquired infection rates.

            Sehulster: Another interesting question.  I think the presence of a continual sanitizing property on a surface would be very beneficial to healthcare facilities, but the real proof of this would come from a well-designed epidemiological study that documents a reduction in healthcare-associated infections.  Such a study should be a prospective study that carefully identifies potential confounding variables and controls for them.

At one point in an EPA conference several years ago, manufacturers noted that the levels of microbial contamination on most hard surfaces was less than 10[6] per unit area, and they asked the question  -  why do we have to prove a 6 log reduction for their product to be registered.  Many manufacturers indicated that if they could promote sanitizers for hard surfaces in hospitals, the contact times would shorten significantly.  Perhaps the copper surfaces brings this debate to the forefront.

 Abrasion/Chemical Treatment: The proposed protocol includes a requirement that the carriers made from the copper or copper alloy undergo both an abrasion step and a chemical treatment step in order to simulate actual conditions of use and to evaluate how abrasion and/or chemical treatment might affect the level of antimicrobial activity.  Note that some disinfectant and sanitizer products, as well as some cleaning agents, contain chelating agents (e.g., EDTA) intended to bind free metal ions.
 Please comment on whether abrasion and/or chemical treatment is likely to affect the level of antimicrobial activity displayed by a product.  If not, please explain why.  If so, please comment on how well the proposed abrasion step and chemical treatment step reflect the likely range of actual use conditions.  To the extent that the simulated conditions do not reflect the likely range of actual use conditions, please comment on whether the additional requested information (quantitative and qualitative) about the durability of the product is sufficient to assess the potential for physical disruption of the product surface after long term use.

            Arduino: The abrasion and chemical treatment steps would represent aging and potential changes to the surfaces with use over time.  Since these surfaces will be routinely cleaned on a daily basis followed by a more thorough cleaning after patient discharge at least cleaned daily and the a more thorough cleaning (terminal cleaning) after patient discharge.

            In this same vane it might be useful to know if there are changes in the amount of loss of active agent over time or improvement by releasing more copper ions.

            Does wiping surfaces (eg. commercially available disinfectant wipes; microfiber cleaning cloths with a hospital grade disinfectant, etc) and scratching the surface increase the likelihood of copper coming off in the leachate.  What is the average life span of these surfaces (especially of this is a coating). So abrasion and chemical treating would simulate the potential use of the product.  It may he helpful to look at the market and to pick the most common disinfectant cleaners, disinfectants in use at healthcare facilities. (I would suspect that Sodium hypochlorite solutions, quats, and peroxide containing products would be the most widely used)

            Bozue: It would be the assumption of this reviewer that at some point, the abrasion and/or chemical treatment would begin to reduce the antimicrobial effect of the copper product due to breakdown of the material.  The warranty statement states that it would be wear-resistant and durable as long as the product remains in place and use as directed.  However, for the testing protocol, the material would be exposed to 180 treatments over a 12 week process, which seems like this would be a rather abundant/ challenging treatment prior to bacterial testing and simulating cleaning of material in a real world situation.  The protocol also states the coupons would not be used that show discoloration, pitting, or scratches would no longer be used.  The assumption of the reviewer is that these would be affected in the ability/ expectation to n reach the 99.9% CFU killing.  Should the label for these products also reflect such a caveat?

            Egan: The abrasion treatment may likely affect the level of antimicrobial treatment if the material is a copper-coated surface. The chemical treatment may or may not affect the antimicrobial activity. The labelling claims of this type of material states that cleaning agents typically used for traditional hard, non-porous touch surfaces are permissible. The chemical treatment that will be used in this test should reflect the actual use conditions with these solutions being similar to those utilized on these surfaces. This is not the case with the abrasion treatment. One would not expect to routinely use abrasive materials on these types of surfaces. It would be useful for the product labels to reflect this.  Both of these tests may provide useful information however, the abrasion treatment studies should be used as informational only. The chemical treatment studies should and do reflect actual conditions of use and the material should meet the recommended %r reduction as outlined in the test protocol.
            It will also be useful to review data that the product manufacturers have developed to substantiate the label claims that the antimicrobial activity is effective as long as the life of the product. There may be some situations in which after numerous years, the activity is either decreased or eliminated. It would be important to have this data.

            Sehulster: A surface that is no longer smooth can provide topography that may shield microorganisms present in the cracks, etc. from full contact with the antimicrobial product, in essence resulting in a diminished antimicrobial result.  With a copper-clad surface, this diminishing result could be avoided if the copper layer is deeper than the superficial rough surface.  If the cracks and depressions in the surface extend beyond the depth of the copper layer, we would expect that the performance of the product will be diminished.

Since the incorporation of an abrasive and chemical treatment represents a departure from a more traditional method of evaluating a product's antimicrobial properties. I think the agency should ask for as much manufacturer information about the physical durability of the product, both copper-clad and spray-on versions, as can be provided.  In addition, the agency should pose the durability question to the manufacturers of steel surfaces and equipment for comparison.  Somewhere between these two pieces of information you should get a reasonable idea of the wear-and-tear of hospital surfaces and how quickly this occurs.  What evaluation did you use to shorten the abrasive and chemical treatment time as described in your document?

 If you think that abrasion and/or chemical treatment may affect antimicrobial efficacy, but that the proposed protocol does not adequately evaluate the potential for such effects, please offer advice on how to change the protocol (e.g., what process and/or chemical solutions should be used to treat a carrier) so that the protocol will adequately evaluate the level of antimicrobial activity of a product.  Please comment specifically on whether the use of products containing chelating agents is likely to affect the level of antimicrobial activity of solid metal and metal alloy products. Also, please comment specifically on whether the cleaning step (thoroughly rinse with DI water) between exposure cycles is sufficient to remove residual chemical solutions (solutions A, B and C).

            Arduino: Have you considered measuring copper concentration in solutions (leachate) used to remove cells from the carriers.  Abrasion and scratching of the surfaces might release copper from the impregnated surfaces.

            I also believe that the protocol should employ a chelator (eg., thioglycollate, EDTA, etc) to remove any potential carry over of copper ions into the culture media thus preventing growth and yielding lower colony counts (so potentially greater log reduction).

            I think before going too far that a comparison of the method with and with-out chelation would be necessary.  If the results of that comparison study are equivalent, then the use of chelators may not be necessary.

            Bozue: The cleaning steps with DI water rinse should be adequate to remove residual chemicals between the treatment steps.

            Egan: The abrasion treatment may or may not affect the efficacy- depending on if the force due to the physical removal of the copper surface is sufficient to remove the copper (if copper coated). The studies as outlined in the protocol should be performed to determine this.  It is doubtful that the products even if they containing chelating agents would affect the level of antimicrobial activity.  A thorough rinsing with DI should be sufficient to remove chemical residues.

            Sehulster: I think the inclusion of the abrasive and chemical treatment in the protocol is appropriate, but it would be important to know how thick the copper layer is.  A rough surface that is still copper-clad would still have antimicrobial activity, but if the cracks and crevices get down to base metal that could diminish the antimicrobial activity.  Furthermore, the deeper the cracks and crevices, the more likely you will have the opportunity for soil levels to build, thereby adding another factor to protect microbes.  With regards to the presence of chelating agents, I know they do have an effect on metal ions in solution, in essence removing them from solution, but I do not know much about their action on metal ions in hard metal.  With regards to whether or not the use of water to thoroughly rinse the chemicals away from the carriers is effective, my sense is that this rinse step should be adequate.  If the question involved the presence of soil or organic matter on the surface, then I would think that a surfactant would be needed.

All of this discussion about abrasive and chemical treatment center on the copper-clad surfaces and items.  With the spray-on products, I would think the manufacturers would have to advise their customers to reapply the product frequently to counter surface abuse over time.  How long does the effect remain active after the spray-on product is applied?  It would seem to me that any physical or chemical abuse to the treated surface would remove the product from the surface.

 Residual/Continuous Activity:  Residual/continuous activity over time is claimed to be one attribute inherent to copper and copper alloy products.
 Some technology developers would like to claim that solid copper and copper alloy products provide "residual/continuous activity."  Please comment on whether the proposed protocol is capable of determining if copper and copper alloy products provide such activity, and if not, what changes to the proposed protocol (e.g., instituting repeated inoculations of the carrier) would provide data to evaluate such activity.

            Arduino: Current protocol addresses the log reduction in within an hour however, these products claim to have continuous activity.  It would seem appropriate to re-challenge the coupons (re-inoculate) at some time period after their culture and determine whether the log reductions are similar log reductions over time.

            For antimicrobial containing dressings FDA recommend that manufacturers follow ASTM E2315-03 Standard Guide for Assessment of Antimicrobial Activity Using a Time-Kill Procedure or an equivalent method. Test results should demonstrate at least a 4 log reduction.  So this type of testing is performed on items such as antimicrobial impregnated respirators (eg. copper-silver, copper, iodine).  Efficacy for testing must show 4 log reduction within 1 hr (impregnated drapes, bandages, respirators, surgical masks, etc).

            The other testing that FDA accepts is performance testing (bench and animal) so for silver impregnated catheters they look at controls (not coated or impregnated) vs impregnated and evaluate colonization over time (difference here is that they are fluid based assessments, eg central venous or urinary catheters).

            So continuous activity might require a sequential re-inoculation of carriers to see whether the same log reduction occurs.

            Bozue: It is the opinion of this reviewer that this protocol could be revised to address the residual/continuous activity over time.  For instance, the current protocol requires that the copper containing coupons could not be reused but for some reason, the stainless steel coupons are reused.  Perhaps the copper coupons could be reused and go through additional  abrasion/ chemical treatment steps then have the bacterial CFU added again to test repeated applications of the bacteria and if the 99.9% reduction is still attainable.

            Egan: As the protocol is written, a claim of continuous activity would not be able to be tested. Longer term studies over at least several years would be needed to determine if the products can provide continuous activity over the length of the product life. To be able to determine continuous activity for a shorter period of time, additional repeated inoculation studies would be necessary.

            Sehulster: If the manufacturer is claiming antimicrobial action over time, then a protocol would need to be developed to evaluate this.  I don't think the current protocol lends itself to measuring a continual action.  One problem to be addressed is this - is there an endpoint for a protocol that attempts to validate "continual" activity?

In my opinion, before the agency can develop a test protocol for continual antimicrobial action, it should spend some time to establish a definition for this phenomenon, and propose it as part of the pesticide registration regulatory program after a Federal Register comment period.  Once you have defined the property and established measureable, discreet aspects to that property, then you can develop a method to measure and validate this.


[Federal Register: August 31, 2009 (Volume 74, Number 167)]
[Notices]
[Page 44841]
[DOCID:fr31au09-73]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. ER09-1514-000]

New York Independent System Operator; Notice of FERC Staff
Attendance

August 25, 2009.
    The Federal Energy Regulatory Commission (Commission) hereby gives
notice that on September 3, 2009 at 11 a.m. (EST) and/or Wednesday,
September 9, 2009 at 2 p.m. (EST) members of its staff will participate
in WebEx Training sessions to review the enhancements associated with
the transactions aspect of the NYISO Energy Market, specifically,
Trading Hubs. Information on the training sessions is available on the
NYISO's Web site at https://nyiso.webex.com. Sponsored by the NYISO,
the training sessions are open to all market participants, and staff's
attendance is part of the Commission's ongoing outreach efforts. The
training sessions may include discussions relating to matters at issue
in the above captioned proceeding. For further information, contact
Connie Caldwell at<EMAIL_ADDRESS>(202) 502-6489 or Jeffrey
Honeycutt at<EMAIL_ADDRESS>(202) 502-6505.

Kimberly D. Bose,
Secretary.
[FR Doc. E9-20942 Filed 8-28-09; 8:45 am]

BILLING CODE 6717-01-P


[Federal Register Volume 78, Number 231 (Monday, December 2, 2013)]
[Notices]
[Pages 72137-72139]
[FR Doc No: 2013-28725]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-70943; File No. SR-CBOE-2013-115]

Self-Regulatory Organizations; Chicago Board Options Exchange,
Incorporated; Notice of Filing and Immediate Effectiveness of a
Proposed Rule Change To Amend the CBSX Fees Schedule

November 25, 2013.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(the ``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given
that on November 21, 2013, Chicago Board Options Exchange, Incorporated
(the ``Exchange'' or ``CBOE'') filed with the Securities and Exchange
Commission (the ``Commission'') the proposed rule change as described
in Items I, II, and III below, which Items have been prepared by the
Exchange. The Commission is publishing this notice to solicit comments
on the proposed rule change from interested persons.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend the Fees Schedule of its CBOE Stock
Exchange. The text of the proposed rule change is available on the
Exchange's Web site (http://www.cboe.com/AboutCBOE/CBOELegalRegulatoryHome.aspx), at the Exchange's Office of the
Secretary, and at the Commission's Public Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange included statements
concerning the purpose of and basis for the proposed rule change and
discussed any comments it received on the proposed rule change. The
text of these statements may be examined at the places specified in
Item IV below. The Exchange has prepared summaries, set forth in
sections A, B, and C below, of the most significant aspects of such
statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    CBSX proposes to amend its Maker fees for transactions in all other
securities (securities other than the ``Select Symbols'', of which
there currently are none) priced $1 or greater. Currently, such fees
are assessed on the following scale: \3\
---------------------------------------------------------------------------

    \3\ The parentheticals (1) and (5) in the scale refer to
footnotes in the CBSX Fees Schedule. Footnote (1) reads:
     These rates apply to all transactions in securities priced $1
or greater made by the same market participant in any day in which
such participant adds (for Makers) or removes (for Takers) the
established amount of shares (or percentage of TCV, as applicable)
or more of liquidity that is determined in the chart above for each
tier. Market participants who share a trading acronym or MPID may
aggregate their trading activity for purposes of these rates.
Qualification for these rates will require that a market participant
appropriately indicate his trading acronym and/or MPID in the
appropriate field on the order.
    Footnote (5) reads:
    ``TCV'' means total consolidated volume calculated as the volume
reported by all exchanges and trade reporting facilities to a
consolidated transaction reporting plan. Volume from Maker
executions in the Select Symbols (priced $1 or greater) will count
towards a market participant's % of TCV.
    The Exchange does not propose to amend either Footnotes (1) or
(5).

------------------------------------------------------------------------

------------------------------------------------------------------------
Maker (adds less than 0.08% of TCV of liquidity   $0.0018 per share
 in one day) (1)(5).
Maker (adds at least 0.08% but less than 0.16%    $0.0017 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds at least 0.16% but less than 0.24%    $0.0016 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds at least 0.24% but less than 0.42%    $0.0015 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds 0.42% or more of TCV of liquidity in  $0.0014 per share
 one day) (1)(5).
------------------------------------------------------------------------

    The Exchange proposes to break up the 0.24%-0.42% tier into two
separate tiers at 0.33%, with Maker transactions in the 0.33%-0.42%
tier being assessed a lower fee of $0.0014 per share (currently, Maker
transactions in such tier would be assessed the same fee as in the
0.24%-0.33% tier, which is $0.0015 per share). The Exchange also
proposes to add a 0.42%-0.52% tier, with Maker transactions in that
tier being assessed a fee of $0.0013 per share (which is lower than the
$0.0014 per share fee that Maker transactions in that tier currently
are assessed). Finally, the Exchange proposes to add a tier for Makers
who add 0.52% of TCV of liquidity in one day or more, with such
transactions being assessed a lower fee of $0.0012 per share (which is
lower than the $0.0014 per share fee that

Maker transactions in that tier currently are assessed). As such, upon
effectiveness of the proposed changes, the Maker fees for transactions
in all other securities priced $1 or greater will be as follows:

------------------------------------------------------------------------

------------------------------------------------------------------------
Maker (adds less than 0.08% of TCV of liquidity   $0.0018 per share
 in one day) (1)(5).
Maker (adds at least 0.08% but less than 0.16%    $0.0017 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds at least 0.16% but less than 0.24%    $0.0016 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds at least 0.24% but less than 0.33%    $0.0015 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds at least 0.33% but less than 0.42%    $0.0014 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds at least 0.42% but less than 0.52%    $0.0013 per share
 of TCV of liquidity in one day) (1)(5).
Maker (adds 0.52% or more of TCV of liquidity in  $0.0012 per share
 one day) (1)(5).
------------------------------------------------------------------------

    The proposed changes are aspirational. The Exchange believes that
the proposed new tiers will provide liquidity targets for CBSX market
participants to aspire to reach, and the lowered fees in these new
tiers will provide incentives for such CBSX market participants. The
Exchange believes that the increased liquidity that results will
benefit all market participants, and perhaps enable some such market
participants to reach higher tiers (with the corresponding lower
transaction fees) than they otherwise might.
    The proposed changes are to take effect on December 2, 2013.
2. Statutory Basis
    The Exchange believes the proposed rule change is consistent with
the Act and the rules and regulations thereunder applicable to the
Exchange and, in particular, the requirements of Section 6(b) of the
Act.\4\ Specifically, the Exchange believes the proposed rule change is
consistent with Section 6(b)(4) of the Act,\5\ which requires that
Exchange rules provide for the equitable allocation of reasonable dues,
fees, and other charges among its Trading Permit Holders and other
persons using its facilities. The Exchange believes the proposed fee
(and tier) changes are reasonable because all the proposed changes
involve lowering fees from their current levels (in the tiers created/
affected). There are no fee increases proposed by this proposed rule
change, the affected market participants will certainly prefer to be
assessed lower fees. The Exchange believes that the proposed changes
are equitable and not unfairly discriminatory because, while they
provide for lower fees for market participants who hit certain
liquidity levels than others, the proposed new tiers (and corresponding
lowered fees) are intended to provide liquidity targets for CBSX market
participants to aspire to reach. The Exchange believes that the
increased liquidity that results will benefit all market participants,
and perhaps enable some such market participants to reach higher tiers
(with the corresponding lower transaction fees) than they otherwise
might. Finally, the proposed new fee tiers will be applied equally to
all CBSX market participants.
---------------------------------------------------------------------------

    \4\ 15 U.S.C. 78f(b).
    \5\ 15 U.S.C. 78f(b)(4).
---------------------------------------------------------------------------

B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
impose any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act. CBSX does not believe that
the proposed rule change will impose any burden on intramarket
competition that is not necessary or appropriate in furtherance of the
purposes of the Act because, while they provide for lower fees for
market participants who hit certain liquidity levels than others, the
proposed new tiers (and corresponding lowered fees) are intended to
provide liquidity targets for CBSX market participants to aspire to
reach. The Exchange believes that the increased liquidity that results
will benefit all market participants, and perhaps enable some such
market participants to reach higher tiers (with the corresponding lower
transaction fees) than they otherwise might. Finally, the proposed new
fee tiers will be applied equally to all CBSX market participants. The
Exchange does not believe that the proposed rule change will impose any
burden on intermarket competition that is not necessary or appropriate
in furtherance of the purposes of the Act because the proposed changes
are intended to attract greater liquidity and make CBSX a more
attractive marketplace for market participants on all exchanges
(thereby enhancing competition). To the extent that the proposed
changes make CBSX a more attractive marketplace for market participants
on other exchanges, such market participants may elect to become CBSX
market participants. Also, the proposed changes only apply to trading
on CBSX.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    The Exchange neither solicited nor received comments on the
proposed rule change.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    The foregoing rule change has become effective pursuant to Section
19(b)(3)(A) of the Act \6\ and paragraph (f) of Rule 19b-4 \7\
thereunder. At any time within 60 days of the filing of the proposed
rule change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is necessary or
appropriate in the public interest, for the protection of investors, or
otherwise in furtherance of the purposes of the Act. If the Commission
takes such action, the Commission will institute proceedings to
determine whether the proposed rule change should be approved or
disapproved.
---------------------------------------------------------------------------

    \6\ 15 U.S.C. 78s(b)(3)(A).
    \7\ 17 CFR 240.19b-4(f).
---------------------------------------------------------------------------

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File Number SR-CBOE-2013-115 on the subject line.

Paper Comments

     Send paper comments in triplicate to Elizabeth M. Murphy,
Secretary, Securities and Exchange Commission, 100 F Street NE.,
Washington, DC 20549-1090.

All submissions should refer to File Number SR-CBOE-2013-115. This file

number should be included on the subject line if email is used. To help
the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street NE.,
Washington DC 20549, on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of such filing also will be available
for inspection and copying at the principal offices of the Exchange.
All comments received will be posted without change; the Commission
does not edit personal identifying information from submissions. You
should submit only information that you wish to make available
publicly. All submissions should refer to File
    Number SR-CBOE-2013-115, and should be submitted on or before
December 23, 2013.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\8\
---------------------------------------------------------------------------

    \8\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

Kevin M. O'Neill,
Deputy Secretary.
[FR Doc. 2013-28725 Filed 11-29-13; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 77, Number 186 (Tuesday, September 25, 2012)]
[Notices]
[Pages 58998-58999]
[FR Doc No: 2012-23545]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-D-0597]

Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Draft Guidance for
Industry: Oversight of Clinical Investigations: A Risk-Based Approach
to Monitoring

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing that a
proposed collection of information has been submitted to the Office of
Management and Budget (OMB) for review and clearance under the
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by October
25, 2012.

ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be faxed to the Office
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer,
FAX:<PHONE_NUMBER>, or emailed to<EMAIL_ADDRESS>All
comments should be identified with the OMB control number 0910-New and
title ``Draft Guidance for Industry on Oversight of Clinical
Investigations: A Risk-Based Approach to Monitoring; Availability.''
Also include the FDA docket number found in brackets in the heading of
this document.

FOR FURTHER INFORMATION CONTACT: Ila S. Mizrachi, Food and Drug
Administration, 1350 Piccard Dr., PI50-400B, Rockville, MD 20850, 301-
796-7726<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.

Draft Guidance for Industry: Oversight of Clinical Investigations: A
Risk-Based Approach to Monitoring--(OMB Control Number 0910-New)

    Description of Respondents: Respondents to this collection of
information are sponsors that monitor clinical investigations.
    Burden Estimate: The draft guidance is intended to assist sponsors
of clinical investigations in developing risk-based monitoring
strategies and plans for investigational studies of medical products,
including human drug and biological products, medical devices, and
combinations thereof. The guidance is intended to make clear that
sponsors can use a variety of approaches to fulfill their
responsibilities related to monitoring investigator conduct and the
progress of investigational new drug (IND) or investigational device
exemption (IDE) studies. The guidance describes strategies for
monitoring activities performed by a sponsor, or contract research
organizations (CROs), that focus on the conduct, oversight, and
reporting of findings of an investigation by clinical investigators.
The guidance recommends strategies that reflect a risk-based approach
to monitoring that focuses on critical study parameters and relies on a
combination of monitoring activities to oversee a study effectively.
The guidance specifically encourages greater reliance on centralized
monitoring methods, where appropriate.
    Sponsors are required to provide appropriate oversight of their
clinical investigations to ensure adequate protection of the rights,
welfare, and safety of human subjects and the quality and integrity of
the resulting data submitted to FDA.\1\ As part of this oversight,
sponsors of clinical investigations are required to monitor the conduct
and progress of their clinical investigations.2 3 The
regulations are not specific about how sponsors are to conduct
monitoring of clinical investigations and, therefore, are compatible
with a range of approaches to monitoring. FDA currently has OMB
approval for the information collection required under part 812 (OMB
control number 0910-0078) and part 312, including certain provisions
under subpart D (OMB control number 0910-0014).
---------------------------------------------------------------------------

    \1\ Part 312 (21 CFR part 312), subpart D, generally
(Responsibilities of Sponsors and Investigators) and part 812 (21
CFR part 812), subpart C, generally (Responsibilities of Sponsors).
    \2\ Section 312.50 requires a sponsor to, among other things,
ensure ``proper monitoring of the investigation(s)'' and ``that the
investigation(s) is conducted in accordance with the general
investigational plan and protocols contained in the IND.''
    \3\ Also see Sec. Sec.  312.53(d), 312.56(a), 812.40, and
812.43(d).
---------------------------------------------------------------------------

    However, the collections of information associated with this draft
guidance that are not currently approved under OMB control numbers
0910-0014 or 0910-0078 are as follows:
    Development of Comprehensive Monitoring Plan: Section IV.D of the
draft guidance recommends that sponsors develop a prospective, detailed
monitoring plan that describes the monitoring methods,
responsibilities,

and requirements for each clinical trial. The plan should provide those
involved in monitoring with adequate information to effectively carry
out their duties. All sponsor and CRO personnel who may be involved
with monitoring, including those who review and/or determine
appropriate action regarding potential issues identified through
monitoring, should review the monitoring plan. The components of a
monitoring plan are described in the draft guidance, including
monitoring plan amendments (i.e., the review and revision of monitoring
plans and processes for timely updates). FDA understands that sponsors
currently develop monitoring plans; however, not all monitoring plans
contain all the elements described in the guidance. Therefore, our
following burden estimate provides the additional time that a sponsor
would expend in developing a comprehensive monitoring plan based on the
recommendations in the guidance. We estimate that approximately 88
sponsors will develop approximately 132 comprehensive monitoring plans
in accordance with the draft guidance, and that the added burden for
each plan will be approximately 4 hours to develop, including the time
needed for preparing monitoring plan amendments when appropriate (a
total of 528 hours).
    Voluntary Submission of Monitoring Plans to FDA: Section IV.D of
the draft guidance permits sponsors to voluntarily and prospectively
submit their monitoring plans to the appropriate Center for Drug
Evaluation and Research (CDER) review division and request input from
the division's clinical trial oversight component (sponsors of
significant risk device studies are already required under Sec.
812.25(e) to submit and maintain written procedures for monitoring). We
estimate that approximately 22 sponsors will submit approximately 33
monitoring plans to CDER for feedback and that each submission will
take approximately 2 hours to complete (a total of 66 hours).
    In the Federal Register of August 29, 2011 (76 FR 53683), FDA
published a 60-day notice requesting public comment on the proposed
collection of information. The following is a summary of the comments
and FDA's response to the comments for the two collections of
information associated with the draft guidance that are not currently
approved by OMB.
    Development of Comprehensive Monitoring Plan:
    FDA received comments that the guidance lacks specific information
on development and initialization of risk assessment plans, appropriate
mitigation plans, and execution of mitigation plans through the
monitoring plan. Addition of use of risk management tools, along with
potential applications for using risk-based monitoring strategies would
help facilitate implementation.
    In response to the comments, FDA included additional detail in the
final guidance in an effort to enhance the quality, utility, and
clarity of the information collected. Specifically, FDA included
additional detail on the development of a monitoring plan, which
focuses on the important and likely risks, identified by the risk
assessment, to critical data and processes. In addition, FDA included
additional guidance on the steps involved in performing a risk
assessment and references to tools and methodologies that can be used
to perform a risk assessment. FDA clarified that the guidance does not
provide comprehensive detail on how to perform a risk assessment.
    FDA received several comments that the guidance should specify that
it is acceptable for monitoring plans to reference existing standard
operating procedures (SOPs) or other documents.
    The draft guidance specifies that a monitoring plan may reference
existing policies and procedures in order to minimize the burden of the
collection of information.
    Voluntary Submission of Monitoring Plans to FDA:
    FDA received numerous comments that the lack of specific details
about FDA review of the monitoring plans early enough in the IND
process could delay startup of clinical trials. In addition, numerous
comments requested a detailed process or procedure.
    Although the draft guidance stated that CDER was considering
establishing processes through which sponsors could voluntarily submit
monitoring plans for CDER feedback, CDER has concluded that CDER does
not have the resources necessary to commit to such a review at this
time. CDER is exploring the possibility of a pilot program in this area
in the future.
    FDA estimates the burden of this collection of information as
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
        Draft guidance on monitoring clinical investigations            Number of      responses per     Total annual   Average  burden    Total hours
                                                                       respondents       respondent       responses      per  response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Development of Comprehensive Monitoring Plan.......................              88              1.5              132                4              528
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Dated: September 17, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-23545 Filed 9-24-12; 8:45 am]
BILLING CODE 4160-01-P