Triangle Pharmaceuticals Vol

Pharniaceuticals 114ugust2001 Dockets Management Branch (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 RockwIle. MD 208.52 John E. Dillberger, ./.. DVM, Ph.D. 1. Dir@or, Toxicolpgy and Preclinical Pharmacology -’ re: Immunotoxicology Evaluation of Investigational New Drugs (Jr..j:ICUT~‘~~/clj301Q~~~T~.~O~~ Dear Madams and Sirs: I write to submit comments on the draft guidance entitled hmunotoxicology Evaluation of Investigational New Drugs. My comments are presented in the attached table by line number of the document in .pdf format. With appreciation for the opportunity to comment upon the document and trusting you will find my suggestions of some use, I am Sincerely yours, .lohn Dillberger, DVM, PhD Diplomate, American College of Veterinary Pathologists Diplomate, American Board of Toxicology C -3 By MaiZ: 4611 University Drive . P.O. Box 50530 Durham, NC 27717-0530 By Express Courier: 4 University Place 4611 University Drive Durham, NC 27707 Edephone: (919) 402-2653 Facsimile: (919) 493-5925 email: dillbeje@tripharm.com \ +j ,.,- c IssuelConcernlRationale for Proposed Change Proposed Revision List of adverseeventscould be betterorganized This guidancediscussesthree categoriesof and the events betterdefined. adverseeffects on the immunesystem: The 5 categoriesin the list could be reducedto 3 1. Immunosuppression, definedas a functional categoriesof potentiallyadverseeffectson impairmentof the immunesystemthat is immunesystemfunction. In particular,the adversein the contextof the drug’s intended distinctionbetweenwhat is called ‘antigenicity’ use. and ‘hypersensitivity’ fuzzy and distinguishing 2. Immunostimulation, is definedas a functional the two doesn’thelp readersor the FDA decide enhancement the immunesystem that is of upon immunotoxicity evaluationschemesor adversein the contextof the drug’s intended interpretthe resultsof such schemes. use. The proposedrevisionmakesthe types of 3. Inappropriately directedimmuneresponse, potentiallyadversereactionsclearerand defines definedas an immunereactionagainstan them as functionalratherthan structural inappropriate target,which is adversein the changes. contextof the drug’s intendeduse. This categoryincludesinductionof an immuneresponseto the drug or its metabolitesor l an autoimmuneresponse. Theguidanceoughtto spell out clearlyin which circumstances sponsorshouldconsideror a conductimmunotoxicity studieseven when standardnonclinicaltoxicity studies revealno evidenceof immunotoxicity.For example: ‘Regardlessof the presenceor absenceof evidenceof immunotoxicity nonclinicaltoxicity in studies,additionalimmunotoxicity studiesshould ?econductedif: l l ;G--- c “Evidenceofinimmunotoxicitycan usuallybe observed standardnonclinicaltoxicology I 50-51 , 1 ! studies...‘I “Signs of immunotoxicity nonclinicalstudies in shouldbe evaluatedto.determinewhethermore specificstudies would be useful.” Thesesentencesimply that additionalspecific immunotoxicity studieswill be the exception ratherthan the rule, but don’t spell out what the exceptionsare. SectionIII does so, but in a generalway. Clear, precise,specific languageis needed. 190-228 The drug is administeredtopicallyor by inhalation,or The drug concentratesin immunesystem cells or tissuesor l Patientswith HIV or a relatedimmunedisease will use the drug.” If neitherof these situationsexists, then additional immunotoxicity studies should be consideredonly if thereis evidenceof immunotoxicity nonclinical in toxicitystudies. Decidingwhetherto conduct additionalstudies and whjch studiestoconduct will be influencedby severalconsiderations.” Theguidancethen could go on to discuss immunotoxicity ‘markers’as it does now. l 1Li;;;o”‘. i 76 99-100 j 102-103 I Fir---134-136 Issue/Concern/Rationalefor Prop&i ChangeT Proposed Revision “Potentialimmunotoxiceffects should be evaluated “Potentialimmunotoxiceffects should be I in terms of both dose and, when data are extrapolatedto humansby comparingsystemic available,systemicexposure. Wherepossible, exposureor, if data are unavailable,by comparing dose comparisonsto clinical use should be dose expressedon a body surface area basis,” basedon relativebody surfaceareas.” First sentencesuggestssystemicexposure comparisonis better than dose comparison, makingthe secondsentenceambiguous. The proposedrevisionclarifiesthat in the absence of systemicexposurecomparison,dose comparisonbasedon bodysurfacearea is preferredto dose comparisonbasedon body mass. ‘I...effectsof the drug that are stress inducing.” 0..effectsof the drug that are stress-induced.” Typographical error. . “Hematoiogicevidenceof myelosuppression, Severalclinical conditionslisted as evidenceof myelosuppression this bullet pointdon’t belong in such as such as leukopenia(aloneor as a here,and othersthat belonghere are omitted. componentof pancytopenia), neutropenia, Specifically,anemiaand thrombocytopenia lymphopenia, monocytopenia. or suggestnot immunosuppression insteadan but inappropriately directedimmuneresponse (immune-mediated RBC or plateletdestruction). D This bullet point could be betterworded. “Evidenceof structuralchangesin immune system organsor tissues, such as reduced spleenor thymusweight or histopathologic alterationsin lymph nodes,thymus,spleen, bone marrow,or epithelia-associated lvmphoid . ’ tissues (GALT,BALT,etc.).” This bullet point lists a parameternot routinely Jnless you are intendingto tell sponsorsto include measuredin nonclinicaltoxicity studies. Thus, it serumimmunoglobulin concentrationroutinelyin probablyshouldbe omittedhere. he clinical pathologytests run as part of general oxicity studies,then omit the bullet point in line ‘Althoughdecreasesin serum immunoglobulin IO9and the sentencein lines 134-136. might be considereda relativelyinsensitive indicatorof immunosuppression, this measurement usefulbecauseit can be readily is incorporatedinto the standardbatteryof clinical pathologytests.” s FDA suggestingthat this parameter(serum immunoglobulin concentration), acknowledged as of doubtfulusefulness,shouldbe incorporated routinelyinto the clinical pathologytests run as part of generaltoxicity studies? If so, then I would suggestrethinkingthis idea. LLine No(s). Issue/Concern/Rationale for Proposed Change 111-116 This paragraphis unnecessary.Any sponsor developinga drug will understandfrom the outset whetheror not immunosuppression a desirable is effect or an undesirable within the contextof one the drug’s intendedclinical use. This paragraphdescribesanemiasand blood dyscrasias,and seemsto try to link reductionsin bloodcell counts (e.g. anemia)to immunosuppression.Then in the last sentence, it talks about an “autoimmune antidrug or antibodycomponent.” Either I or the authorsare confusedhere. To my knowledge, immunosuppression not associatedwith blood is dyscrasias,except in two situations: lymphopeniawhen the immunosuppression is l a consequenceof lymphocytedeathor . granulocytopenia when the immunosuppression a consequence is of impairedgranulocytopoiesis increased or granulocytedeath. I‘. studies to determinepotentialmechanismsare encouraged.” Ambiguouslanguage--eitherthe situationrequires that mechanisticstudies be done, or it doesn’t. FDA needsto provideclear guidanceto sponsors here. ‘. when...infectionsare observedin nonclinical toxicologystudies,the cause of infectionsshould be determined.” Thisis not routinelydone now, so the advice constitutesa ‘new’ practice. Is FDA suggesting that any infectionbe cultured’ and the responsiblemicroorganism identified? That seemsthe only interpretation this sentence. of This paragraphsays that a sponsorshould consideraddingunspecifiedimmunotoxicity assessmentsto the StageC-F reprotoxicitystudy (pre- and post-nataldevelopmental toxicity study) if a drug likely will be used by pregnantwomen. This is too vagueto constituteguidance. FDA needsto bite the bullet here and suggesta particularassessment. r . “. . . Proposed Revision Omit this paragraph. 138-150 I I Omit this paragraphthat seemsto link anemias and blooddyscrasiasto immunosuppression.If want to mentionsomethingabout lymphopenia and granulocytopenia correlatedwith as immunosuppression, fine-but present then paragraphis misleadingif not outrightwrong. 1 t 162-163 Decideif the situationcalls for additional mechanistic studiesor if it doesn’t,and say so. 206-207 suggestinga ‘new’ practicein generaltoxicology studiesin the midst of a guidancedocumenton mmunotoxicity probablyisn’t the best way to make sponsors aware. If FDA does indeedwish this new’ practiceadopted,then flag it up in a text box )r “Summaryof SuggestedNew Practices”section atthe end of the document. Choosea specific parameter/assessment/endpoint and state unequivocally sponsorsshould that measureit in Stage C-F reprotoxicitystudy, if that is the agency’sintent. If not, then omit this paragraph. I 217-222 L Line No(s). Issue/Concern/Rationale for Proposed Change 226-228 “Becauseof the presumedincreasedsusceptibility to drug-associated immunotoxicity patients of with impairedimmunefunction[in patients infectedwith HIV or a ‘relatedimmunedisease’], extra nonclinicaleffort to detect immunotoxic effects is warranted.” Actually, I would reasonjust oppositely. Patients knownto have an ‘immunosuppressive’ disease alreadyare beingmonitoredintensivelyfor potentialimmunosuppression.This is the one drug-relatedrisk that can’t sneak up on them. I don’t see the rationalefor singlingout drugsto be used in such patientsfor increasedscrutiny-on the contrary,I would insteadsingleout for greaterscrutinydrugs to be used in patients whose immunesystemsare presumednormal. These patientsare most likely to be caughtoffguard and harmedby an unexpected immunosuppressive effect. / “Undercertaincircumstances,..” . The circumstancesaren’tdetailedand they should be. This is too vagueto provideguidanceto sponsors. 231, 272, As mentionedalready,sectionsV (Antigenicity), VI j and 429 (Hypersensitivity), VII (Autoimmunity) and each discuss an immuneresponsethat is inappropriately targeted-either to the drug itself, to a metabolite,to a haptencreatedby interactionof drug/metabolite a host with molecule,or to a host molecule. The distinctions betweenthe labels hypersensitivity, antigenicity, and autoimmunityare fuzzy and of no nonclinical relevance. Theessentialpoint is that we have no good nonclinicaltests to predictthis sort of inappropriately targetedimmuneresponsein people. Tests do exist for evaluatingpotential contact sensitization/hypersensitivity, even but these aren’tconsideredvery predictive. Nhile the discussionencompassedin these three sections is fine, the documentneedssomewhere to clearly spell out what findings,if any, in generaltoxicity studieswould suggesta potential for an inappropriately targetedimmuneresponse and what specificadditionalstudies,if any, would a sponsorshouldconsideror conductto follow up. c T Proposed Revision I would suggestthat drugs intendedfor use in immunocompromised patientsnot be treated differentlyfrom drugsto be used in other sorts of patients. Detailthe circumstances have in mind. you ?e-thinkand re-writethe materialin sectionsV, VI, xtd VII, payingparticularattentionto clearly definingterms/labelsand also to clearly spelling )ut when sponsorsshouldconsiderconducting additional studiesand what specific assessments :heyshouldmake in such studies. Give consideration down’playing to distinctionsamong :hethree sectionsand insteademphasizingthat all :hreeare facets of an underlyingproblem;pecifically,that drug administrationleadsto an nappropriately targetedimmuneresponsewith adverse consequences. \ 1 Issue/Concern/Rationalefor Proposed Change 491-492 Proposed Revision “If a drug is expectedto be used in pregnant women incorporation immunotoxicology the of in ICH Stage C-F reproductive toxicologystudy should be considered.” Section1V.C.reads“Whenwarrantedby observationin nonclinicaltoxicologystudies, additionalstudiesto determinepotentialdrug effects on immunefunctionshouldbe considered...The importanceof follow-up . immunefunctionstudiesfor overallsafety assessmentdependson the intendeduse of the drug. If a drug is likely to be used in pregnant women...immunotoxicology determinations the in ICH Stage C-F reproductive toxicologystudy should be considered.” Thisseemsto say that if a drug shows evidenceof immunotoxicity generaltoxicity studiesand is in lkely to be used in pregnantwomen,then immunotoxicity assessmentshouldbe includedirI the Stage C-F reprotoxicitystudy. iowever, SectionIX seemsto contradictthis by saying that “If a drug is expectedto be used in pregnantwomen,incorporation of immunotoxicology the ICH Stage C-F in reproductivetoxicologystudy shouldbe considered.” This seemsto say that a drug that will be used in pregnantwomenshouldhave an immunotoxicity assessmentin Stage C-F studies regardlessof whetheror not there are indications of generaltoxicity. AppendixI impliesthe same thing. No suggestedtext, but needto clarify the apparent contradiction. j 190-228 491-492 $ ;< 8 $ ” 33 9 ” J, By Mail: 4611 University Drive P.O. Box 50530 Durham, NC 27717-0530 > .j _ <. $ By Express Courier: 4 University Place 4611 University Drive Durham, NC 27707