http://exhibits.library.stonybrook.edu/mfp/files/original/a3efd0dec017d78d45a3657aa373d8fc.pdf c40045dc04aa881fa68a7430065e22ac PDF Text Text mTJflVW wan; J:wm&m 7383-582 Miran 213%, 1973 Gerald Klermnn. M.D., Profaauor or Paychiutry, Harvard Mbdiaal School. Erich Lindemsnn fihntal Health Ccntar flovarnnunt Center. Bosfion, ”has. 0211h. Dear Gerry, Follawing are coma comments on tbs ACflF task force notes of 6th deruary. 1973 regarding both the ganoral connidcrations and tbs proposal for evaluating antideyrcnsnnt drugs. my comment: may also be relevant to the notes by Uhlcnhuth and Wittenborn. l D While etio of base of at the general utnxamnnts alicit criticism. I am confused by the mission. safety are different tram guidelines fbr necessary differences in rules :0: phase by «aperioncad clinicians from rulaa for approval and little Guidelines for testing efficacy. There are I and donatinding studicl phase III general clinical surveys by an army of technicians. and phase IV clinical trials by hosts of practitioners. I read the guncrnl eonsidnrations, these seem recanted on utudics - varifieatien a! efficacy in small tangles II»!!! phll. A: by techniainns. What or tbs apoainl issues of (9.) identifying clinical populations (phase I) (b) doslgc usasuruuent (a) plmiologiou affects including toxicity? In the guidelinoa. the seloetion of degraaaod patients is sacred no a lymgtau, cauglcx. and a diseasa. and rouolvuu tbs dilamms by approving all fibula. I belicve these distinction. to be inpartanm,and while thn identification of homogeneous yopulaiiona for phnso III-IV studio: in a difficult chore, it is any that neeaa eumhnsia. Thane diltinetions are Ivan were important in phage I trials. where hnt¢ro§enaona populations should be encouraged, and thc data presented not as atumiaticul "salamia" but an eaaa roeords. t �‘Dr. Gerald Klernen ~2~ Mirth alet. 1973 interrelation of eymptem, syndrome, or disease end intervention. (The eeee‘studiee by Klein make e unique contribution in this regard, and eupport for such studies is warranted). Again, the distinction of goele of eeeh study dictates distinction es to methods, and I suggest that the guidelines than: on different ”phases" with different guidelines. (Fer another opinion, see focueaed en the Ballister Iencloeed)). 23 Digtineticn of dogaae Differences in dbeervetiene. particularly as to efficacy. are related not only to the tergut symptom and population seleeted, but delivery of adequate doses of the agent to target urgent. Repcrts of wide differeneee in blood levels with thymoleptiel and lithium, when patients ere given the same dosages, has led to Ipeeuletion (bout genetic differences in metabolite effecting therepeutie results. While genetic and metabolic differences may indeed operete, the inteke, ebeorption, and the influenee of feeding éoeege ere eimpler. more mechanical issues that reqtire study. As with the utility of blood lithium, and blood DPH levels, perhaps the recommendations should include comments that where physiologic indieee exist, therapeutic studies should include concurrent dosage—index measures: at e minimum, daily (or more frequent) urine end'blood levels; and, so frequent heart rate. EKG, or cerebral bioelnetric measures where these may reflect tissue levels. Cerebral bioeleetrie measures, reflecting the effect or an agent on e target argue most directly in antidepressant therapy, are the best index of changes in cerebral aetivity, end here wider a plieatione than the guidelines reflect. (Cerebral potential [EEG studies also ellov en identification and classification of antidepressant, thymoleptie, end euphorient drugs, peovidins a guideline as to the related _ comparison treatment). 31_Heeeg;ee of To some eecegtenee of e new antidepressant, only some cardiotemicity or to effect the lens of the gain it to have wuuld toxigity to find eye, serve eoeiety little. I have been coneerned by the neglect er eerdiec toxicity in early eveluetiens. for example, with thioridesine and meeoridesiae. An evaluation that does not coetraet e profit-east eeeounting is e poor evaluation: to estimate effieeey is limited if it does not eentrest with the esteblished, "effective“ standard. Thus. the guidelines may suggest that change scores of behaviortl measures ehauld be evelueted in the same net as ehensee in blood. cardiac, cerebral, ete. memes. (m. after item: 1 and 2 [page h], there should be en eeseeeuent of "neeendary" effects). (In this regard. item: h, 5, 6, 7 ere clearly poet~eveluetion indiees, useful to the technicians and elinical researchers, but net relevent to evaluation in pheneIIIIII efficacy and safety). - �“It: wanna — 1mw— r,..,w.°4-1,‘ ' wm‘7e<»-.‘ varnn—s ‘E‘F'V-W Dr. Gerald new ~3— march 21». 1973 There is a particular prdblan in assessing antidepreeaants: the ”standard" is not well aeeepted. fer imiyremine and amitriptyline, MAO. and EGT are each queted by different evaluator! far different purposes. Fbr a "unJor" antidepressant. it may have he be contrasted with ECT. Fer the othere,'with imipramine. The guidelines might auggeet when to use which contrast. and perhaye discard any continued use of MAO inhibitors aa a standard. The eeparation of phaae of atuiy and heterogeneous, case studies fer phase 13 emphasis on homogeneous population: fur phase II, III; distinctions of dosage and physiologic indieee; and eoetuprofit analyses fer toxic ayumtome are questions that are alto lacking in the antiwanxiety guidelines. fine notes by Vittefiborn reflect an interest in a very late phase of clinical testing. and.yet he attempts to approach the relevant inauea. .Aa I read his eaten. hie emphasis is on phase III, large aeele testing ~ he netee the frequent diffieulty in dosage. washout, etc. that are also relevant to the issue a! antidayreaeente. Perhaps the guidelines are only focuaeed on phase III~IV testing these notee are inappropriate. Perhape phase I trials require different guidelines, and such a separation an Wittenborn suggests; then be useful in separating and clarifying the guidelines. er the Cenmittee vieh an elaboration of these thoughts. I will try to amplify than with more specific suggestions. of goal may Sheuld you aincerely yours. w<.z-¢nuv.v.-ur~vrr r-uv ‘1’\“-r_""l7 fink . Md). N Protester of Psychiatry "var-qr. MF/iJ 3Q. To B. WittOnbOm. Ph.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Klerman, Gerald L. 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