1EPA Evaluation ofPet Spot-On ProductsAnalysis and Mitigation PlanMarch 17, 2010Ms. Lois Rossi, MS, Director, Registration DivisionDr. Kit Farwell, DVM, DABT Health Effects DivisionMs. Kimberly Nesci, MS, Registration Division2Outline•Background•Analysis•Risk management•Next steps•Questions and answers3Background•Spot-On Products•What are they?•How are they applied?•Why are they registered?•EPA Evaluation•Why, what triggered this?•When?4Background•From 2007 to 2008, total numbers of incidentsincreased by about 53%•2007 Incidents•About 1.9% of the incidents were deaths•About 4% of the incidents were deaths and majorincidents•2008 Incidents•About 1.4% of the incidents were deaths•About 3% of the incidents were deaths and majorincidents•In 2008, there were 270,000,000 doses sold(0.00016 incident per dose)5Background•April 16, 2009, press advisory•Concurrent with a Canadian press advisory•Messages•EPA is intensifying its evaluation of pet spot-onproducts•EPA acknowledged the importance of the products•EPA advised consumers to use caution whenapplying and watch for adverse reactions•EPA advised consumers on what to do if adversereactions occur6Background•May 5, 2009, Registrant Meeting•EPA discussed incidents being reported•EPA discussed the ongoing intensive reviewand information needs•EPA provided a summary of the meetingonline on our Web page•No decisions were made7Background•After the May 5, 2009, meeting•Received enhanced reporting information•Established an expert EPA veterinarian team•Analyzed data and additional information•Collaborated and partnered with The Foodand Drug Administration’s (USFDA) Center forVeterinary Medicine (CVM) and Canada's PestManagement Regulatory Authority (PMRA)•Held a three-day meeting with CVM andPMRA to peer review EPA’s analysis8Analysis•Objective:To describe the nature ofthe incidents and to identify anysusceptible subpopulations or usepatterns associated with increased risk9Analysis – Review Process•Veterinary Team:•Assembled for the purpose ofevaluating these spot-onincident data•Composed of 6 DVMs and other experienced reviewersacross OPP•Chaired by Kit Farwell, DVM•Review Process:•Primary Review conducted by a technical reviewer•Secondary Review conducted by an alternate reviewer•Internal Peer Review by Veterinary Team•External Scientific Peer Review with PMRA Incident andToxicology teams and USFDA CVM10Analysis - Data Received•Enhanced incident reporting included:•Product and background information:•EPA Registration #, product name, lot #, formulationtype, where purchased, active ingredients, weightrange for product, date, state, registrant case #•Pet information:•species, breed, age, sex, weight, route of exposure,how applied, body system, clinical signs, time toonset, duration, veterinary treatment, first time used,misuse, other drug or pesticide used, preconditions,EPA severity code, certainty index, outcome•Spreadsheet cell with text narrative of incident11Analysis – Data Reviewed•Many additional sources of data used in a“Weight-of-Evidence” approach•Incident data•EPA received and analyzed data from eight companies•EPA standardized the format of the data received•Companion animal safety studies•Toxicology database in laboratory animals•Acute Studies•Dermal Toxicity•Pharmacokinetic Data•Literature provided by international expert veterinarian12Analysis – Data EvaluationRecord•The primary technical reviewer prepared dataevaluation records (DERs) and all DERs weretechnically peer reviewed internally and externally.•The DERs assembled the enhanced incident data andavailable animal toxicology information for specificproducts.•DERs were developed for spot-on products thatrepresented a majority of the total incidents received.13Analysis – Incident DataStandardization•Incident data submitted in spreadsheets by the registrantsvaried in the format and the information provided•Each spreadsheet was standardized by EPA so that thedata could be compared•Records were used:•If they included registration numbers•If the incident occurred in the United States•If only one product used on the animal•If multiple reports reflected thesame incident, only one was used•If only one pet was reported to be experiencing the adverse effect•If they included species type14Analysis – Data Evaluation•Key Parameters Evaluated•Severity : dogs and cats•Use not in accordance with label directions: underage, under-weight, wrong species•# of incidents by gender•Age•Body weight•Product weight range, where appropriate•Breed•Body system affected and/or clinical signs15Analysis – Data EvaluationSeverity in dogs and cats•Severity in Dogs and Cats•The percentage of incidents for each severity codewere reported by product.•The severity classifications:•D-A: Death or euthanasia•D-B: Major (life threatening effects or resulted inresidual disability)•D-C: Moderate (more pronounced or prolonged thanminor classification, treatment may have beenrequired•D-D: Minor (minimally bothersome effects whichresolved rapidly)•Adapted from Pesticide Registration Notice 98-3, April 3, 199816Analysis – Data EvaluationUse not in accordance with label directions•Assessed•Cats exposed to dog products•Use on pet weighing less than weight rangeon product label•Use on pet younger than age on label17Analysis – Data EvaluationSex and Age•Gender: assessed percent of incidents•Age: assessed percent of incidents foreach severity code•No gender differences were attributed totreatment with any spot-on•Most dog incidents occurred in dogs <3years old18Analysis – Data EvaluationBody Weight and Breed•Body weight: assessed percent ofincidents for each severity code•Breed•assessed percent of incidents by breed•this information was compared to theAmerican Kennel Club (AKC) ranking fornumber of registrations per year19Analysis – Data EvaluationProduct Weight Range•Assessed percent of incidents in dogs weighingless than the weight range on product label•For some dog products, assessed:•Percent of incidents in dogs weighing less than thelowest weight range•Percent of incidents in dogs in lower 1/2 of that weightrange•Percent of incidents in dogs in upper 1/2 of thatweight range20Analysis – Data EvaluationProduct Weight Range, continued•Did not assess weight range for catsbecause weight ranges were very wideand/or had no lower limit21Analysis – Data EvaluationBody Systems and Clinical Signs•Examples of reported organ systems andclinical signs:•Dermal (irritation and scratching)•Gastrointestinal (vomiting and diarrhea)•Neurological (tremor, depression, seizure)•Ocular (tearing, redness)•Respiratory (cough)22Analysis – Inert Ingredients•Inert ingredients are chemicals addedwith active ingredients to formthe final product formulation. These may be of health concern assome inert ingredients result in:•Enhanced dermal absorption•Skin sensitization•Species-specific toxicity to cats•A specific review of the potentialrisks posed by inert ingredients wasinitiated if the incident data indicated a concern with a particularproduct•Currently, a product cluster was not identified that would indicate that a formulationposed a unique risk compared to other products with similar active ingredients•As part of this review, the Agencyidentified all inert ingredientsincluded in these spot-on products and identified any known orsuspected inert ingredient of potential health risk•The Agency will continue to evaluatethe safety concerns that may beassociated with inert ingredients23Results of the Analysis•Overall Findings•Most incidents were minor, but all analyzedproducts had deaths & major incidentsreported•Types of effects - organ systems mostcommonly affected were dermal,gastrointestinal, and nervous system•Labels often have warnings but, in somecases, warnings are not specific, hard to reador buried in the text24Results of the Analysis•Dog Findings•Small breed dogs were adversely affected by someof these products more frequently than larger dogs.•Weight/dose ranges may be too wide for someproducts (smaller animals get more activeingredient per pound).25Results of the Analysis•Cat Findings•Misuse or inadvertent exposure of dog products tocats is a major problem in the United States andglobally.•Label warnings against use of dog products on catsare not working and do not provide adequateprotection to prevent incidents in cats.26Results of the Analysis•Safety Testing Requirements•Companion animal safety data do not appear topredict the toxicity seen in the incident reports.•Need for adequate testing requirements to addressthe following:•Differences between individual dogs,•Longer-term exposure (as a result of the repeated dosing),•Route of exposure (for example, dermal and oral exposuresfrom grooming).•Collaborating with PMRA and FDA27Questions?28Risk Management•Agency concluded, based on the analysis,that mitigation is necessary to preventunreasonable adverse effects•Regulatory Action Plan – EPA will pursuethe following:•Product-specific, immediate further restrictions•Tighter regulation•Public outreach campaign29Risk Management:Further Restrictions•Address dosing concerns•Pursuing label and/or packaging changes thatwould result in more narrow pet weight rangesper vial size30Risk Management:Further Restrictions•Address concerns about cat exposure to dogproducts•Pursuing label changes that prohibit the use of thesame brand names for both dog and cat products•Determining appropriate, clear labels statements toaddress concerns with cat exposure to dog products•as a result of direct application or•as a result of interactions between dogs and cats afterapplication of dog products31Risk Management:Further Restrictions•Address concerns about label clarity•Address product specific concerns•Pursuing further label restrictions•Pursuing other changes, as needed, based onindividual product assessments (DERs)32Risk Management:Further Restrictions•Address uncertainties about inertingredients•Pursuing disallowing alternate formulations•Determining whether additional information oncertain inerts is needed and, if so, obtainingthat information•When inerts with suspected toxic effects areidentified, EPA will not allow the use of thesechemicals in pet products33Risk Management:Tighter Regulation•Pursue standardized adverse eventreporting•Standard format•Standard content•Analysis of the information•Will allow EPA to efficiently continue postmarket surveillance of these products34Risk Management:Tighter Regulation•Pursue standardized sales reporting•Will allow EPA to accurately comparenumbers of incidents between products35Risk Management:Tighter Regulation•Revise Data Requirements - taking steps tobring data requirements in line with FDA’srequirements for similar products•Will allow EPA to be consistent with FDA, includingpre-market clinical trials•Will allow EPA to more thoroughly assess the safetyof these products prior to registration•Will allow effective post-market surveillance36Risk Management:FDA and EPA RequirementsCurrent EPA RequirementsCurrent FDA RequirementsPre-MarketAnimalSafety StudyGuideline No: 870.7200Title: Companion Animal SafetyNumber of Animals: 6 per sex per doseLevel of Concern: 5XOther: Harmonized withprevious FDA/CVMGuidance #33Guideline No: 185 (VICH GL43)Title: Target Animal Safety for VeterinaryPharmaceutical ProductsNumber of Animals: 4 per sex per doseLevel of Concern: 5XOther: International harmonizationPre-MarketClinical TrialsNoneGuideline No: 85 (VICH GL9)Title: Good Clinical PracticeNumber of Animals~200 (where 1/2 are positivecontrol). Represents populationsof actualpetsrather than only test beagles. Informs labeling andcontributes to the overall approvaldecision.Post-MarketSurveillanceAggregate summary reporting of summarynumbers of adverse effects under FIFRASection 6(a)(2).Generally only used to triggera more detailed review.Ten veterinarians and other professional staffevaluate detailedadverse events, particularly fornew products. Findings may result in changes toproduct, label, insert, andcommunication with vetsand the public.37Risk Management:Tighter Regulation•Conditional Registrations•Future pet spot-on registrations (newproducts) and amendments to existingregistrations will contain appropriateconditions and time limitations•Will allow EPA to conduct appropriate postmarket surveillance38Risk Management:Potential Implementation Mechanisms•Anticipated further restrictions•Will be meeting with individual registrants to discussindividual products and product lines•Considering preparing a guidance document•Tighter regulation•Will be discussing with Canada’s PMRA•Will be discussing with FDA’s CVM•Will be obtaining public input•May require changes to rules and guidelines or otherregulatory process39Public Outreach Campaign•The Agency is taking steps to initiate a multiprong communication campaign•inform the public and other interested parties of theresults of the investigation•steps the public can take to ensure safe use of petflea and tick products40Questions?41Today’s Activities•Registrant Meeting 9:30 am – 11:30 am•Press Release•Web page update•Public Webinar 4:00 pm – 6:00 pm42Next Steps•Registrant Meetings (summaries will bedocketed)•FR Notice•Docket:EPA–HQ–OPP–2010–0229•www.regulations.gov•60-day public comment period•Implementation•Announcements of any additional changes43Contact information•For press inquiries:•Dale Kemery•kemery.dale@epa.gov•For all other inquiries:•Kimberly Nesci, Registration Division, Office ofPesticide Programs•pets@epa.gov•Web page•http://www.epa.gov/pesticides/health/petproductseval.html44Thank You