Glidande medelvärde klinisk kemi

Asperger syndrom: ett kliniskt konto Lorna Wing, från MRC: s socialpsykiatri enhet, Psykiatrisk institut, London Synopsis - De kliniska egenskaperna, kursen, etiologi, epidemiologi, differentialdiagnos och hantering av Asperger syndrom beskrivs. Klassificering diskuteras och motiveras för att inkludera syndromet, tillsammans med tidig barndomsautism, i en bredare grupp av tillstånd som gemensamt har nedsatt utveckling av social interaktion, kommunikation och fantasi. De många mönster av abnormt beteende som orsakar diagnostisk förvirring innefattar en som ursprungligen beskrivits av den österrikiska psykiatriken Hans Asperger (1944, 1968, 1979). Namnet han valde för detta mönster var autistisk psykopati med hjälp av det senare ordet i den tekniska meningen med en abnormitet av personlighet. Detta har lett till missförstånd på grund av den populära tendensen att jämföra psykopati med sociopatiskt beteende. Av detta skäl är det neutrala termen Asperger syndrom att föredra och kommer att användas här. Inte långt innan Aspergers originalpapper om detta ämne uppträdde 1944, publicerade Kanner (1943) sitt första konto om syndromet han kallade tidig infantilautism. De två villkoren är på många sätt likartade, och argumentet fortsätter att vara om de är sorter av samma underliggande abnormitet eller separata enheter. Kanners arbete är allmänt känt internationellt, 9Aspergers bidrag är betydligt mindre känt utanför den tyska litteraturen. De enda publicerade diskussionerna om ämnet på engelska som är kända för den nuvarande författaren är av Van Krevelen (1971), Isaev amp Kagan (1974), Mnukbin amp Isaev (1975) (översättning från ryska), Wing (1976), Chick et al 1979), Wolff Amp Barlow (1979) och Wolff Amp Chick (1980). Dessutom, en bok av Bosch där autism och Asperger syndrom jämförs, ursprungligen på tyska 1962, har översatts till engelska (Bosch, 1962). Ett papper som gavs av Asperger i Schweiz 1977 visade sig i en engelsk version (Asperger, 1979). Robinson amp Vitale (1954) och Adams (1973) gav kliniska beskrivningar av barn med beteende som liknar Asperger syndrom, men utan att hänvisa till denna diagnos. I det föreliggande dokumentet kommer syndromet att beskrivas, illustreras med fallhistorier och differentialdiagnosen och klassificeringen diskuteras. Kontot baseras på Aspergers beskrivningar och i 34 fall, varierande i ålder 5 till 35 år, personligen undersökt och diagnostiserad av författaren. Av dessa hade 19 historien och den kliniska bilden av syndromet i mer eller mindre typisk form och 15 visade många av funktionerna vid den tidpunkt de sågs, men de hade inte alla den karakteristiska tidiga historien (se nedan). Sex av dem i serien identifierades som ett resultat av en epidemiologisk studie av tidig barndomspsykoser i Camberwell-området i sydöstra London (Wing Amp Gould, 1979). Resten hänvisades till författaren för diagnos - 11 av sina föräldrar, genom familjedoktor, två av huvudlärare och 15 av andra psykiatriker. Följande allmänna beskrivning innehåller alla de vanligaste funktionerna. Men som med alla psykiatriska syndrom som endast kan identifieras från ett mönster av observerbart beteende finns det svårigheter att bestämma vilka som är nödvändiga för diagnos. Variationer förekommer från person till person och det är sällsynt att i alla fall hitta alla detaljer som anges nedan. Den kliniska bilden Illustrativa fallhistorier baserade på barns och vuxnas syn på den nuvarande författaren finns i bilagan. I hela papperet hänvisas siffrorna inom parantes till dessa historier. Aspergers beskrivning av syndromet Asperger noterade att syndromet var mycket vanligare hos pojkar än hos tjejer. Han trodde att det aldrig blev erkänt i spädbarn och vanligtvis inte före det tredje året av livet eller senare. Följande beskrivning är baserad på Aspergers-konton. Barnet börjar vanligtvis tala vid den ålder som förväntas hos normala barn, medan promenader kan vara försenade. Ett fullständigt kommandot om grammatik förvärvas förr eller senare, men det kan vara svårt att använda pronomen korrekt, med substitutionen av den andra eller tredje för de första personformulären (nr 1). Innehållet i tal är onormalt, tenderar att vara pedantiskt och består ofta av långa förkunskaper om favoritämnen (Nr.2). Ibland upprepas ett ord eller en fras igen och igen på ett stereotypiskt sätt. Barnet eller vuxen kan uppfinna några ord. Subtila verbala skämt förstås inte, men enkel verbal humor kan uppskattas. Icke-verbala aspekter av kommunikation påverkas också. Det kan vara litet ansiktsuttryck förutom med starka känslor som ilska eller elände. Sångintonation tenderar att vara monotont och dronning eller överdriven. Gester är begränsade, annars stora och klumpiga och olämpliga för det medföljande talet (nr 2). Förståelse av andra människors uttryck och gester är dålig och personen med Asperger-syndrom kan missförstå eller ignorera sådana icke-verbala tecken. Ibland kan han allvarligt blicka in i andras ansikte och leta efter den mening som utesluter honom. Kanske är den mest uppenbara egenskapen försämring av tvåvägs social interaktion. Detta beror inte främst på en önskan att dra sig ur social kontakt. Problemet härrör från brist på förmåga att förstå och använda reglerna för socialt beteende. Dessa regler är oskrivna och oskrivna, komplexa, ständigt förändrade och påverkar tal, gest, hållning, rörelse, ögonkontakt, val av kläder, närhet till andra och många andra aspekter av beteende. Graden av skicklighet inom detta område varierar bland vanliga människor, men de med Asperger syndrom ligger utanför det normala intervallet. Deras sociala beteende är naivt och märkligt. De är medvetna om sina svårigheter och strävar även till att övervinna dem, men på olämpliga sätt och med signaler saknar framgång. De har inte den intuitiva kunskapen om hur man anpassar sina tillvägagångssätt och svar för att passa in i andras behov och personligheter. Vissa är överkänsliga för kritik och misstänksamma för andra människor. En liten minoritet har en historia av ganska bisarra antisociala handlingar, kanske på grund av sin brist på empati. Detta gällde fyra av nuvarande serier, varav en skadade en annan pojke under sina experiment på kemikaliers egenskaper. Förhållanden med motsatt kön ger ett bra exempel på den mer allmänna sociala ojämnheten. En ung man med Asperger syndrom observerar att de flesta av hans samtidiga har tjejvänner och så småningom gifter sig och har barn. Han vill vara normal i detta avseende, men har ingen aning om hur man anger sitt intresse och lockar en partner på ett socialt acceptabelt sätt. Han får fråga andra för en lista över regler för att prata med tjejer, eller försöka hitta hemligheten i böcker (nr 1). Om han har en stark sexdriven kan han närma sig och röra eller kyssa en främling, eller någon som är mycket äldre eller yngre än sig själv, och som en följd finner sig i trubbel med polisen eller han kan lösa problemet genom att bli ensam och dra tillbaka . Repeterande aktiviteter och motstånd mot förändring Barn med detta syndrom tycker ofta om att spinna föremål och titta på dem tills rörelsen upphör, i mycket större utsträckning än normalt. De tenderar att bli intensivt knutna till särskilda ägodelar och är väldigt olyckliga när de är borta från välbekanta platser. Bromsmotorrörelser är klumpiga och ohämmade. Inställning och gångarter verkar udda (Nr.1). De flesta personer med detta syndrom (90 av de 34 fallen som nämns ovan) är dåliga på spel som involverar motoriska färdigheter, och ibland påverkar de verkställande problemen förmågan att skriva eller rita. Stereotypade rörelser av kropp och lemmar nämns också av Asperger. Färdigheter och intresse De med syndromet i de flesta typiska former har vissa färdigheter såväl som funktionsnedsättningar. De har utmärkta rote minnen och blir intensivt intresserade av ett eller två ämnen, såsom astronomi, geologi, ångtågets historia, släktforskningens genealogi, busstidtabeller, förhistoriska monster eller tecknen i en tv-serie, till uteslutandet av allt annat. De absorberar alla tillgängliga fakta angående deras utvalda fält och talar om det i längden, huruvida lyssnaren är intresserad eller inte, men har lite förståelse för betydelsen av de fakta som de lär sig. De kan också utmärka sig brädspel som behöver ett bra rote-minne, till exempel schack (No.2), och vissa har musikalisk förmåga. Sjuttiofem procent av nuvarande författarserier hade speciella intressen av detta slag. Men vissa har specifika lärandeproblem, som påverkar aritmetiska färdigheter, läsning eller, som nämnts ovan, skrivande. Erfarenheter i skolan Denna kombination av skol - och kommunikationsbrist, och vissa speciella färdigheter ger ett intryck av markerad excentricitet. Barnen får vara onödigt mobbade i skolan och blir följaktligen oroliga och rädda (nr 1 och 2). De som är mer lyckliga i skolorna som de deltar kan accepteras som excentriska professorer och respekteras för sina ovanliga förmågor (nr 4). Asperger beskriver dem som otillfredsställande elever eftersom de följer sina egna intressen, oavsett lärarens instruktioner och resten av klassens aktiviteter (nr 3 och 4). Många blir så småningom medvetna om att de skiljer sig från andra människor, särskilt när de närmar sig tonåren och blir följaktligen överkänsliga för kritik. De ger intrycket av ömtålig sårbarhet och en patetisk barnsinnighet, som vissa finner oändligt röra och andra bara exasperating. Ändringar av Aspergers konto För närvarande har författaren noterat ett antal ytterligare föremål i utvecklingshistoriken, som inte registrerats av Asperger, vilket ibland kan uppstå genom lämplig förhör av föräldrarna. Under det första året av livet kan det ha varit brist på det normala intresse och nöje i människa som borde vara närvarande från födseln. Babbling kan ha varit begränsad i kvantitet och kvalitet. Barnet kanske inte har dragit uppmärksamhet på saker som händer omkring honom för att dela intresset med andra människor. Han kanske inte har tagit med sig sina leksaker för att visa sina föräldrar eller besökare när han började gå. I allmänhet saknas den intensiva strävan att kommunicera i babble, gest, rörelse, leenden, skratt och så småningom tal som karaktäriserar den normala bebisen och småbarnet (No.3). Imaginativ låtsas spel uppstår inte alls hos några av dem som har syndromet, och hos dem som har låtsat spela är det begränsat till en eller två teman, upptagna utan variation, om och om igen. Dessa kan vara ganska utarbetade, men eftersträvas repetitivt och involverar inte andra barn om inte de senare är villiga att följa exakt samma mönster. Det händer ibland att de teman som ses i detta pseudo-låtsaspel fortsätter som uppmärksamhet i vuxenlivet och utgör huvudfokus för en imaginär värld (se Richard Lets historia i Bosch 1962). Det finns också två punkter som den nuvarande författaren skulle vara oense med Aspergers observationer. Först säger han att tal utvecklas innan han går och hänvisar till ett särskilt intimt förhållande till språk och mycket sofistikerade språkliga färdigheter. Van Krevelen (1971) betonade detta som en differentieringspunkt från Kanners tidiga barndomsautism, där vanligtvis gås utvecklas normalt eller till och med tidigare än genomsnittet, medan talets början fördröjs markant eller aldrig uppträder. Men lite mindre än hälften av de nuvarande författarna gick mer typiska fall av Asperger syndrom på vanlig ålder, men var långsamma att prata. Halvleken pratade normalt men var långsam att gå, och en gick och pratade båda vid de förväntade tiderna. Trots eventuell god användning av grammatik och en stor ordförråd avslöjar noggrann observation över en tillräckligt lång tid att innehållet i talet är fattigt och mycket av det kopieras otillbörligt från andra människor eller böcker (nr 3). Språket som används ger intrycket av att bli lärd av Rote. Betydelsen av långa och dunkla ord kan vara kända, men inte de ord som används varje dag (No.5). Egenheterna hos icke-verbala aspekter av tal har redan nämnts. För det andra beskrev Asperger människor med sitt syndrom som förmåga till originalitet och kreativitet i sitt utvalda fält. Det skulle vara mer sant att säga att deras tankeprocesser begränsas till en smal, pedantisk, bokstavlig, men logisk, resonemangskedja. Den ovanliga kvaliteten på deras tillvägagångssätt härrör från tendensen att, som utgångspunkt för den logiska kedjan, välja någon aspekt av ett ämne som sannolikt inte kommer att uppstå för en normal person som har absorberat den nuvarande inställningen i sin kultur. Vanligtvis är resultatet olämpligt, men en gång i taget ger det ny inblick i ett problem. Asperger trodde också att personer med hans syndrom var av hög intelligens, men han citerade inte resultaten av standardiserade intellektuella test för att stödja detta. Som framgår av fallhistoriken i tillägget är de speciella förmågorna huvudsakligen baserade på rote-minne, medan förståelsen av den bakomliggande betydelsen är dålig. De med syndromet saknar uppenbar syn i sunt förnuft. Det måste påpekas att de personer som beskrivs av nuvarande författare alla hade problem med justering eller överlagda psykiatriska sjukdomar som är tillräckligt stora för att kräva hänvisning till en psykiatrisk klinik. Nio hade lämnat skolan eller vidareutbildning. Av dessa var tre anställda, tre hade förlorat sina jobb och tre hade inte fått arbete. Författaren är också bekant, genom sina föräldrar som är medlemmar i National Society for Autistic Children, med några unga vuxna som rapporterat ha några eller alla funktioner i Asperger-syndromet, och som använder sina speciella färdigheter framgångsrikt i öppen anställning. Det skulle vara olämpligt att ge exakta nummer eller inkludera dessa i serien, eftersom författaren inte har tillgång till fallhistorik eller bedömning. Av denna anledning är den serie som beskrivs här förmodligen partisk mot de med svårare handikapp. Kurs och prognos De publicerade kliniska beskrivningarna är av barn och unga vuxna. Inga studier av kursen och prognosen i senare liv finns tillgängliga. Asperger betonade stabiliteten i den kliniska bilden under hela barndomen, ungdomar och åtminstone i det tidiga vuxna livet, förutom den ökning av färdigheter som uppkommit genom mognad. De viktigaste egenskaperna tycks vara ogenomträngliga för effekterna av miljö och utbildning. Han ansåg att den sociala prognosen var generellt bra, vilket innebär att den mest utvecklade tillräckligt långt för att kunna använda sina speciella färdigheter för att få anställning. Han observerade också att vissa som hade särskilt höga förmågor inom området för sina speciella intressen kunde följa karriär inom exempelvis vetenskap och matematik. Som Bosch (1962) påpekade är det möjligt att hitta personer med alla egenskaper som är karakteristiska för Asperger-syndromet annat än normal eller hög intelligens. Detta gällde 20 av serierna som beskrivs här. Om dessa är accepterade som tillhör samma diagnostiska kategori, måste Aspargers ganska hoppfulla syn på prognosen ändras för att ta hänsyn till sådana fall (se fallhistorik för J. G. Bilaga nr.5). Prognosen påverkas också av förekomsten av överlagda psykiatriska sjukdomar. Kliniskt diagnoserbar ångest och varierande grader av depression kan hittas, särskilt i sen ungdom eller tidigt vuxenliv, som tycks vara relaterade till en smärtsam medvetenhet om handikapp och skillnad från andra människor (nr 2 och 3). Wolff amp Chick (1980), i en uppföljningsstudie av 22 personer med Asperger syndrom, rapporterade en som tycktes ha en typisk schizofren sjukdom och en annan i vilken denna diagnos gjordes, men mindre övertygande. Fem av de 22 hade försökt självmord vid tidpunkten för det tidiga vuxna livet. I dagens författarserier ingår 18 som var 16 år och äldre när de sågs. Av dessa hade fyra en affektiv sjukdom fyra hade blivit alltmer udda och återtagna, förmodligen med underliggande depression 1 hade en psykos med illusion och hallucinationer som inte kunde klassificeras Jag hade haft en episod av katatonisk dumhet man hade bisarrt beteende och en obekräftad diagnos av schizofreni och två hade bisarrt beteende, men ingen diagnoserbar psykiatrisk sjukdom. Två av de föregående hade försökt självmord och en hade pratat om att göra det. Dessa två hänvisades på grund av deras problem i att klara kraven i vuxenlivet. Även om det verkar som om risken för psykiatrisk sjukdom i Asperger syndrom är hög är det svårt att dra slutsatser på grund av arten av de prover som studerades. De 13 personer som nämnts ovan, innan de sågs av den nuvarande författaren, hade hänvisats till vuxna tjänster på grund av överlagda psykiatriska förhållanden, så serien var mycket partisk. Wolffs fall var något mindre selektiva eftersom de hänvisades till barn och följde upp i vuxenlivet, men det var ändå kliniker och inte befolkningsbaserade. Asperger (1944) noterade att endast en av hans 200 fall utvecklade schizofreni. Den sanna förekomsten av psykiatriska sjukdomar kan bara beräknas från en epidemiologisk studie, inklusive personer med syndrom som inte hänvisas till psykiatriska tjänster. Även i frånvaro av igenkännlig psykisk störning kan ungdomar vara en svår tid. Utvecklingen av partiell insikt och ökad sexuell medvetenhet kan orsaka mycket olycka (Nr. I) och kan leda till socialt oacceptabelt beteende. Särskilda egenskaper som kan ignoreras hos ett litet barn blir mycket uppenbara hos en ung vuxen. Den grad av anpassning som så småningom uppnåtts förefaller vara relaterad till nivån och de olika färdigheter som finns och också för den berörda individens temperament. God självvård, en speciell förmåga som kan användas i betald anställning och en lugn natur behövs om en person med Asperger syndrom ska bli socialt oberoende. Etiologi och patologi Asperger (1944) ansåg att hans syndrom skulle överföras genetiskt. Han rapporterade att karaktärerna tenderade att inträffa i familjerna, speciellt fäderna till dem med syndromet. Van Krevelen (1971) uppgav att i många fall hade antecedenterna i generationer tillbaka varit mycket intellektuella. I nuvarande författarserien hade 55 fäder som var i professionella eller ledande yrken, men föräldrarnas personligheter studerades inte systematiskt. I många fall sågs moderen ensam. Syftet med intervjun var att diskutera barnets problem, inte att undersöka föräldrarna. Inklusive endast de som berörs av vissa preliminära slutsatser (från kliniska intryck eller bevis från andra källor) visade det sig att 5 av 16 pappor och 2 av 24 mödrar hade i en gradvis grad beteende som liknar det som finns i Asperger syndromet . Inga egenskaper hos den kliniska bilden föreföll vara förknippade med högre eller lägre socialklass, föräldrarnas utbildningsnivå eller deras personligheter. Det är svårt att tolka resultaten om social klass, eftersom de fall som hänvisas till kliniker som har ett särskilt intresse för sådana problem är en utvald grupp, med stark inriktning mot högre social klass och intellektuella yrken i föräldrarna. Schopler et al (1979) och Wing (1980) noterade en liknande bias hos fäderna av klassiskt autistiska barn som hänvisades till kliniker, vilket inte reflekterades i mindre valda grupper med samma diagnos. Fynden om föräldrarnas personligheter måste behandlas med försiktighet på grund av hur de erhölls och bristen på någon jämförelsegrupp. Syndromet kan hittas hos barn och vuxna med historia av för-, penna - eller postnatala tillstånd, såsom anoxi vid födseln, som kan ha orsakat hjärnskador. Detta var sant för nästan hälften av dem som ses av den nuvarande författaren (nr 3 och 4). Mnukhin amp Isaev (1975) ansåg att beteendemönstret berodde på organisk brist på hjärnfunktion. Emotionella orsaker eller onormala barnuppfödningsmetoder har föreslagits, speciellt där föräldrarna eller syskonen uppvisar liknande särdrag hos patienten, men det finns inga bevis för att stödja sådana teorier. Det krävs detaljerade epidemiologiska studier, baserade på totala populationer, för att fastställa vilka, om några av dessa etiologiska faktorer är relevanta. Ingen specifik organisk patologi har identifierats. Inga särskilda abnormiteter i ansikte eller kropp har rapporterats. I barndomen är det fysiska utseendet vanligtvis, men inte alltid normalt. I tonåren och vuxenlivet ger den olämpliga gången, hållningen och ansiktsuttrycket ett intryck av udda. I allmänhet, på psykologisk bedömning, utförs tester som kräver bra rote-minne väl, men underskott visas med de som är beroende av abstrakta begrepp eller sekvensering i tid. Visuo-rumsliga förmågor varierar och poängen på testning kan vara betydligt lägre än de för uttryckligt tal (nr 4). Resultaten av psykologisk testning kommer att beskrivas närmare på annat håll. Som nämnts har inga detaljerade epidemiologiska studier utförts, så att den exakta förekomsten av Asperger syndrom är okänd. En stor svårighet att utforma en sådan studie skulle vara att upprätta kriterier för att skilja syndromet från andra liknande förhållanden, vilket kommer att diskuteras senare. Wing Amp Gould (1979) genomförde en studie där alla psykiskt och fysiskt handikappade barn under 15 år i ett område i London screenades för att identifiera fall av tidig barndomspsykos och allvarlig mental retardation. I denna studie visade två barn (0,6 per 10 000 år yngre än 15) de flesta egenskaperna hos Asperger-syndromet, även om de var i det mildt retarderade området på intelligenstest och 4 (1,1 per 10 000) kunde ha diagnostiserats som autistiska tidigt livet, men kom att likna Asperger syndrom senare. Totalt var 35 000 barn under 15 år i området. Wing Amp Gould använde inte metoder som syftar till att identifiera milda fall av Asperger syndrom, så att alla barn som gick på normal skola och inte hade uppmärksammats av de pedagogiska, sociala eller medicinska tjänsterna inte skulle ha upptäckts. Förekomstvärdet för det typiska syndromet som anges ovan är nästan säkert en underskattning. Syndromet verkar vara betydligt vanligare hos pojkar än hos tjejer. Asperger trodde ursprungligen att det var begränsat till män, men han modifierade denna syn senare (personlig kommunikation). Wolff amp Barlow (1979) nämnde att den kliniska bilden kunde ses hos tjejer. I deras serie var han / hon-förhållandet 9: 1. I nuvarande författarserien fanns 15 pojkar och 4 tjejer med syndromet i ganska typisk form och 13 pojkar och 2 tjejer som hade många av funktionerna. Flickorna tenderade att vara ytligt mer sällskapliga än pojkarna, men närmare observation visade att de hade samma problem med tvåvägs social interaktion. Som med alla villkor som endast kan identifieras från ett mönster av onormalt beteende, där varje element kan uppträda i varierande grad av svårighetsgrad, är det möjligt att hitta personer på gränserna för Asperger-syndromet i vilken diagnosen är särskilt svår. Medan det typiska fallet med lätthet kan erkännas av dem med erfarenhet på fältet, konstateras det i praktiken att syndromet skuggas in i excentrisk normalitet och i vissa andra kliniska bilder. Innan det är mer känt om den underliggande patologin, måste det accepteras att inga exakta avstängningspunkter kan definieras. Diagnosen måste baseras på den fullständiga utvecklingshistoriken och presentera klinisk bild, och inte på närvaron eller frånvaron av enskilda objekt. Normal variant av personlighet Alla egenskaper som karakteriserar Asperger syndrom kan hittas i varierande grad i den normala befolkningen. Människor skiljer sig i deras kompetensnivå i social interaktion och i deras förmåga att läsa icke-verbala sociala signaler. Det finns en lika stor fördelning inom motorfärdigheter. Många som är kompetenta och oberoende som vuxna har speciella intressen som de förföljer med markerad entusiasm. Att samla föremål som frimärken, gamla glasflaskor eller järnvägsmotornummer är socialt accepterade hobbyer. Asperger (1979) påpekade att förmågan att dra sig tillbaka till en inre värld av sina egna speciella intressen är tillgänglig i större eller mindre omfattning för alla människor. Han betonade att denna förmåga måste vara närvarande i stor utsträckning hos dem som är kreativa artister eller forskare. Skillnaden mellan någon med Asperger syndrom och den normala personen som har en komplex inre värld är att den senare deltar på lämpligt sätt i tvåvägs social interaktion ibland, medan den förra inte gör det. Den normala personen, som utarbetar sin inre värld, påverkas emellertid av sina sociala erfarenheter, medan personen med Asperger-syndrom verkar avskuren från effekterna av yttre kontakter. Ett antal normala vuxna har utomordentligt bra rote minnen och till och med behåller eidetiska bilder i vuxenlivet. Pedantiskt tal och en tendens att ta saker bokstavligt kan också hittas hos vanliga människor. Det är möjligt att vissa människor kan klassificeras som lidande av Asperger syndrom eftersom de ligger vid den extrema änden av det normala kontinuumet på alla dessa funktioner. I andra fall kan en viss aspekt vara så märkt att det påverkar hela deras funktion. Mannen som beskrivs av Luria (1965), vars visuella minnen av föremål och händelser var så levande och så permanenta att de störde hans förståelse av deras betydelse, verkade ha uppfört sig inte i motsats till någon med Asperger syndrom. Tyvärr gav Luria inte tillräckligt med detaljer för att möjliggöra en diagnos. Trots att Asperger syndrom verkar slå samman i det normala kontinuumet, finns det många fall där problemen är så markerade att förslaget till en distinkt patologi verkar vara en mer trolig förklaring än en variant av normality. Bristen på empati, ensamhet, udda kommunikation, social isolering och överkänslighet hos personer med Asperger syndrom är funktioner som också ingår i definitionerna av schizoid personlighet (se recension av Wolff amp Chick, 1980). Kretschmer (1925) skisserade några fall historier av skizoidvuxna vuxna, varav en eller två påminner starkt om detta tillstånd, även om han inte tillhandahöll tillräcklig detalj för att säkerställa diagnosen. En ung man hade till exempel inga vänner i skolan, var udda och besvärlig i social interaktion, hade alltid svårt med tal, deltog aldrig i grova spel, var överkänslig och väldigt olycklig när han var hemifrån. Han tänkte på fantastiska tekniska uppfinningar och, tillsammans med sin syster, uppfann en detaljerad imaginär värld. Det är ingen tvekan om att Asperger syndrom kan betraktas som en form av schizoid personlighet. Frågan är om denna gruppering är av något värde. Detta kommer att diskuteras nedan i avsnittet om klassificering. Vuxna med Asperger syndrom kan diagnostiseras som lidande från schizofreni. Differentialdiagnosen av schizofreni har diskuterats någon annanstans (J. K.Wing, 1978). Den största svårigheten härrör från det faktum att schizofreni har definierats löst av vissa och strikt av andra arbetare. Om en lös definition av schizofreni accepteras, baserad endast på egenskaper som socialt tillbakadragande och talproblem, kan man kanske göra ett fall för att inkludera Asperger syndrom i denna grupp. Liksom med schizoid personlighet är frågan om det har några fördelar. Fattigdom av social interaktion och abnormaliteter i tal kan ha många olika orsaker, så diagnosen kronisk eller enkel schizofreni tenderar att täcka en mängd olika förhållanden som har lite gemensamt med varandra. Noggrann observation av tal i Aspergers syndrom beskriver skillnader från tankeblockering och riddarna rör sig i tankar som beskrivs av Bleuler (1911). I Aspergers syndrom kan talet vara långsamt, och det kan finnas irrelevanta eller tangentiella svar på frågor, men dessa problem beror delvis på en tendens att fastna i välskötta konversationsspår istället för att producera nya idéer. Utteranser är alltid logiska, även om de inte är relaterade till frågan eller har sitt ursprung i en ovanlig synvinkel. En ung man frågade då en allmän kunskapsfråga om organiserade välgörenhetsorganisationer, att de gjorde saker för olyckliga människor. De ger rullstolar, stylter och runda skor för personer utan fötter. Det finns en markant kontrast mellan den vaga ullligheten i schizofrenisk tanke och den konkreta, pedantiska tillvägagångssätt som finns i Asperger syndromet. Termen schizofreni kan användas mer strängt. Det kan begränsas till dem som för närvarande eller tidigare har visat de florida första rangsymtom som beskrivits av Schneider (1971). I detta fall vil differentieringen av Asperger-syndrom vila på en noggrann definition av de kliniska fenomenen. Om de inte har en överordnad schizofren sjukdom upplever personer med Asperger-syndrom inte tankeeko, tankeutbyte eller införande, tankeutsändningar, röster som kommenterar deras handlingar, röster pratar med varandra eller känslor som yttre krafter utövar kontroll över sin vilja, känslor eller beteende. Den unge mannen, L. P. (Bilaga nr 2), när han frågade om han hade sådana erfarenheter, gav saken lång och försiktig tanke och sa då: Jag tror att sådana saker är omöjliga. Under klinisk undersökning är det nödvändigt att vara medveten om att förståelsen av abstrakta eller okända koncept är nedsatt i Asperger syndromet. De som har svårare former av handikapp kan ha en vana att svara ja på någon fråga som de inte förstår, det här är det snabbaste sättet att skära samman konversationen. Vissa kan också hämta och repetera fraser som används av andra människor, inklusive andra patienter på sjukhusavdelningen, vilket gör diagnosen ännu svårare. Andra psykotiska syndrom Den tendens som finns hos personer med Asperger-syndrom till känslighet och övergeneralisering av att de kritiseras och blir roliga kan, om de finns i märkt form, misstas för en paranoid psykos. De som är upptagna med abstrakta teorier eller sin egen imaginära värld kan sägas ha delusioner eller hallucinationer. En pojke var till exempel övertygad om att Batman skulle komma fram en dag och ta bort honom som sin assistent. Inget rationellt argument kunde övertyga honom annars. Denna typ av tro kan kallas en illusion, men är nog mer benämnd en övervärderad idé. Det har ingen specifik diagnostisk betydelse, eftersom sådana intensiva tankar kan hittas i olika psykiatriska stater. Svår social uttagsförmåga, ekkopraxi och udda kroppsställningar kan noteras. These may become more marked at times, and then they could be regarded as catatonic phenomena. Such catatonic symptoms can be associated with various conditions (including encephalitis) and, on their own, should not be considered as indicative of schizophrenia. Repetitive interests and activities are part of Asperger syndrome, but the awareness of their illogicality and the resistance to their performance characteristic of the classic case of obsessional neurosis are not found in the former It would be of interest to investigate the relationship between Asperger syndrome, obsessional personality, obsessional illness, and post-encephalitic obsessional conditions. The quietness, social withdrawal, and lack of facial expression in Asperger syndrome might suggest a depressive illness. Shyness and distress when away from familiar surroundings could make an anxiety state a possible diagnosis, or excited talking about a rather fantastic grandiose, imaginary world might bring to mind hypomania. However, the full clinical picture and the early developmental history should clarify the diagnosis. More difficult problems occur when affective illnesses are superimposed on Asperger syndrome. Then a double diagnosis has to be made on the history and present state. Early childhood autism Asperger acknowledged that there were many similarities between his syndrome and Kanners early infantile autism. Nevertheless, he considered they were different because he regarded autism as a psychotic process, and his own syndrome as a stable personality trait. Since neither psychotic process nor personality trait has been defined empirically, little more can be said about whether they can be distinguished from each other. Van Krevelen (1971) and Wolff amp Barlow (1979) agreed with Asperger that his syndrome should be differentiated from autism. They differ in their accounts of the distinguishing features and the impression gained from their papers is that, although there are some differences, the syndromes are more alike than unalike. The variations could be explained on the basis of the severity of the impairments, though the authors quoted above would not agree with this hypothesis. Thus the autistic child, at least when young, is aloof and indifferent to others, whereas the child with Asperger syndrome is passive or makes inappropriate one-sided approaches. The former is mute or has delayed and abnormal speech, whereas the latter learns to speak with good grammar and vocabulary (though he may, when young, reverse pronouns), but the content of his speech is inappropriate for the social context and he has problems with understanding complex meanings. Non-verbal communication is severely impaired in both conditions. In autism, in the early years, there may be no use of gesture to communicate. In Asperger syndrome there tends to be inappropriate use of gesture to accompany speech. In both conditions, monotonous or peculiar vocal intonation is characteristic. The autistic child develops stereotyped, repetitive routines involving objects or people (for example, arranging toys and household objects in specific abstract patterns, or insisting that everyone in a room should cross the right leg over the left), whereas the person with Asperger syndrome becomes immersed in mathematical abstractions, or amassing facts on his special interests. Abnormal responses to sensory input - including indifference, distress and fascination - are characteristic of early childhood autism and form the basis of the theories of perceptual inconstancy put forward by Ornitz amp Ritvo (1968) and of over-selectivity of attention suggested by Lovaas et al (1971). These features are associated with greater severity of handicap, and lower mental age. They are not described as typical of Asperger syndrome, and they are rarely seen in older autistic people with intelligence quotients in the normal range. The one area in which this type of comparison does not seem to apply is in motor development. Typically, autistic children tend to be good at climbing and balancing when young. Those with Asperger syndrome, on the other hand, are notably il1-co-ordinated in posture, gait and gestures. Even this may not be a particularly useful point of differentiation, since children who have typical autism when young tend to become clumsy in movernent and much less attractive and graceful in appearance by the time of adolescence (see DeMyer, 1976, 1979 for a discussion of motor skills in autism and autistic-like conditions). Bosch (1962) considered that Asperger syndrome and autism were variants of the same condition. This author pointed out that, although Asperger and Van Krevelen (1971) listed features in the early history which they thought distinguished the two conditions, in practice these did not cluster into two groups often enough to justify the differentiation. The child in Appendix No. 6 illustrates this problem (see also Everard 1980). Asperger regarded the syndrome he described as a disorder of personality that could be distinguished from other types of personality abnormalities although he recognised the similarities to early childhood autism. Wolff amp Barlow (1979) argued that it should be classified under the heading of schizoid personality. In support of this view, Wolff amp Chick (1980) reviewed the literature in which schizoid characteristics are described. As discussed above, the syndrome can be placed in this group, and further work in this field would be of interest, but, at the moment, classification under this heading has no useful practical implications. Although Wolff amp Chick have listed five features, operationally defined, that they regard as core characteristics of schizoid personality, this term, as generally used, is so vague and ill-defined a concept that it covers a wide range of clinical pictures in addition to Asperger syndrome. The aim should be not to enlarge, but to separate sub-groups from the broad category and thus to increase diagnostic precision. Furthermore, the word schizoid was originally chosen to underline the relationship of the abnormal personality to schizophrenia. The latter can occur in a person with Asperger syndrome, but, as already discussed, there is not firm evidence of a special link between this syndrome and schizophrenia, strictly defined. To incorporate such an untested assumption into the name of the condition must give rise to confusion. The reasons for personality variations are so obscure that classifying Asperger syndrome under this heading does not lead to any testable hypotheses concerning cause, clinical phenomena, pathology or management. A more limited, but more productive, view of the problem is to consider it as a consequence of impairment of certain aspects of cognitive and social development. As mentioned above, Wing amp Gould (1979) carried out an epidemiological study of all mentally or physically handicapped children in one area of London, in an attempt to identify all those with autism or autistic-like conditions, whatever their level of intelligence. The results confirmed the following hypothesis. Certain problems affecting early child development tend to cluster together: namely, absence or impairment of two-way social interaction absence or impairment of comprehension and use of language, non-verbal as well as verbal and absence or impairment of true, flexible imaginative activities, with the substitution of a narrow range of repetitive, stereotyped pursuits. Each aspect of this triad can occur in varying degrees of severity, and in association with any level of intelligence as measured on standardised tests. When all children with this cluster of impairments were examined, it was found that a very few resembled the description given by Asperger and some had typical Kanners autism. A number could, tentatively, be classified as having syndromes described by authors such as De Sanctis (1906, 1908), Earl (1934), Heller (see Hulse, 1954) and Mahler (1952), although the definitions given by these writers were not precise enough for easy identification. The remainder had features of more than one of these so-called syndromes and under the general, but unsatisfactory, heading of early childhood psychosis. The justification for regarding them as related is that all the conditions in which the triad of language and social impairments occurs, whatever the level of severity, are accompanied by similar problems affecting social and intellectual skills. Furthermore, individuals with the triad of symptoms all require the same kind of structured, organised educational approach, although the aims and achievements of education will vary from minimal self-care up to a university degree, depending on the skills available to the person concerned. This hypothesis does not suggest that there is a common gross aetiology. This is certainly not the case, since many different genetic or pre-, peri - or post-natal causes can lead to the same overt clinical picture (Wing amp Gould, 1979). It is more likely that all the conditions in which the triad occurs have in common impairment of certain aspects of brain function that are presumably necessary for adequate social interaction, verbal and non-verbal communication and imaginative development. It is possible that these are all facets of one underlying in-built capacity - that is, the ability actively to seek out and make sense of experience (Ricks amp Wing, 1975). Included in this would be the innate ability to recognise other human beings as distinct from the rest of the environment and of special importance. If this basic skill were diminished or absent, the effects on development would be profound, as is the case in all early childhood psychoses. The full range of clinical material can be sub-divided in many different ways, depending on the purpose of the exercise, but no aetiological classification is possible as yet. Sub-grouping on factors such as level of intelligence (Bartak amp Rutter, 1976) or on degree of impairment of social interaction (DeMyer, 1976 Wing amp Gould, 1979) has more useful practical implications for education and management than any based on the eponymous syndromes mentioned above. In the light of this finding, is there any justification for identifying Asperger syndrome as a separate entity Until the aetiologies of such conditions are known, the term is helpful when explaining the problems of children and adults who have autistic features, but who talk grammatically and who are not socially aloof Such people are perplexing to parents, teachers and work supervisors, who often cannot believe in a diagnosis of autism, which they equate with muteness and total social withdrawal. The use of a diagnostic term and reference to Aspergers clinical descriptions help to convince the people concerned that there is a real problem involving subtle, but important, intellectual impairments, and needing careful management and education. Finally, the relationship to schizophrenia of Asperger syndrome, autism and similar impairments can be reconsidered. Although they are dissimilar in family history, childhood development and clinical pictures, both groups of conditions affect language, social interaction and imaginative activities. The time of onset and the nature of the disturbances are different, but there are similarities in the eventual chronic defect states that either may produce. It is not surprising that autism and schizophrenia have, in the past, been confused. Progress has been made in separating them and it is important to continue to improve precision in diagnosis, despite the many difficulties met in clinical practice. Management and education There is no known treatment that has any effect on the basic impairments underlying Asperger syndrome, but handicaps can be diminished by appropriate management and education. Both children and adults with this syndrome, like all those with the triad of language and social impairments, respond best when there is a regular, organised routine. It is important for parents and teachers to recognise the subtle difficulties in comprehension of abstract language, so that they can communicate with the child in ways he can understand. The repetitive speech and motor habits cannot be extinguished, but, with time and patience, they can be modified to make them more useful and socially acceptable. Techniques of behaviour modification as used with autistic children can possibly be helpful if applied with sensitivity. However, Asperger (1979) expressed considerable reservations about using these methods with children with his syndrome who are bright enough to be aware of and, as Asperger put it, to value their freedom. Education is of particular importance because it may help to develop special interests and general competence sufficiently to allow independence in adult life. The teacher has to find a compromise between, on the one hand, letting the child follow his own bent completely, and, on the other, insisting that he conform. She also has to ensure that he is not teased and bullied by the rest of the class. There is no type of school that is particularly suitable for those with Asperger syndrome. Some have performed well in schools for normal children, while others have managed better in schools for various kinds of handicaps. Educational progress depends on the severity of the childs impairments, but also on the understanding and skill of the teacher. Most people with Asperger syndrome who settle in open employment have jobs with a regular routine. They also have sympathetic employers and workmates who are willing to tolerate eccentricities. In many instances, work has been found by parents who persevere in approaching employers, despite all the difficulties. Finding appropriate living accommodation also presents problems. Living with parents is the easiest solution, but cannot last for ever. Hostels or lodgings with a helpful landlady are the most usual answer. Tactful supervision may be needed to ensure that rooms are kept clean and tidy and clothes are changed regularly. Superimposed psychiatric illnesses, if they occur, should be treated appropriately. Emotional distress in adolescents and young adults due to partial insight may be reduced to some extent by counselling from someone who has a full understanding of the syndrome. Such counselling consists mainly of explanation, reassurance and discussion of fears and worries. The counsellor has to adopt a simple and concrete approach in order to stay within the limits of the clients understanding. Psychoanalysis, which depends upon the interpretation of complex symbolic associations, is not useful in this condition. Parents, in their childs early years, are usually confused and distressed by his strange behaviour. They need a detailed explanation of the nature of his problems if they are to understand and accept that he is handicapped. As mentioned above, the following case histories are those of people who have been referred to psychiatric services. The high achievers mentioned by Asperger (1944) are not represented. This is a typical example of the syndrome. Mr K. N. first presented as a psychiatric out-patient when he was aged 28, complaining of nervousness and shyness. As a baby he was always placid and smiling and rarely cried. He used to lie in his pram for hours, laughing at the leaves on the trees. His mother remembered he did not point things out for her to look at, in contrast to his sister. He continued to be quiet and contented as a toddler. If other children took his toys he did not protest. Walking was somewhat delayed and he was slow in acquiring self-care skills, though not enough for his parents to worry. He began to talk around one year of age. He had several words at this time, but, after seeing and hearing a car crash which startled him, he stopped talking and did not begin again until he was three years old. His parents thought his understanding of speech was normal. K. developed good grammar, though he referred to himself in the third person till 4-5 years old. He has never been communicative. Even as an adult he gives information only if questioned and then replies as briefly as possible. His facial expression and gestures are limited, and his voice is monotonous. As a child he was attached to his mother, he never made any friends, and he was much teased at school. He remains a shy and socially isolated person though he would like to be able to make social contacts. K. had no stereotyped movements, but has always been ill-co-ordinated and very poor at games. He does not swing his arms when he walks. He attended a private school and did well in subjects needing a good rote memory, such as history and Latin, but fell behind at the stage when comprehension of abstract ideas became necessary. He was in the army for a short time, but was not allowed to take part in marches and parades because of his clumsiness and inability to do the right thing at the right time. He was discharged because of these peculiarities. K. did not object to changes imposed by others, but he was, and still is, orderly in his own daily routines and in arranging his own possessions. From early in his life he liked toy buses, cars and trains. He amassed a large collection and would notice at once if a single item were missing. He would also make models with constructional kits. He played with such toys, on his own, for as long as he was allowed to continue. He had no other pretend play and never joined in with other children. The interest in means of transport has remained with him. In his spare time he reads factual books on the subject, watches cars and trains and goes on trips to see trains with fellow train-enthusiasts. He has no interest in fiction or any other type of non-fiction. K. has been employed for many years in routine clerical work. He enjoys his job and his hobby, but is very sad and anxious because he is aware of his own social ineptness and would like to have friends and to marry. He writes many letters to advice columns in magazines, hoping for help with these problems. His concern over what he terms his shyness finally made him ask for help from a psychiatrist. The WAIS gave K. an IQ in the dull normal range, with similar verbal and non-verbal scores. He was particularly poor at sub-tests needing comprehension of a sequence of events. The second case history is also typical, but complicated by severe depression with onset in early adult life. Mr L. P. was admitted to a psychiatric hospital at age 24 because of a suicide attempt. He was born four weeks premature and had feeding problems in the first week or two. He was an easy, placid, rather unresponsive baby who rarely cried. He acquired motor and self-care skills, but his parents later realised that he passed these milestones more slowly than his sister, though they did not worry at the time. His father had a vague premonition that there was something odd about L. but not enough to seek advice. He did not begin to speak until he was three years old, but this was attributed to the fact that the family was bilingual. However, by the time he went to school he was speaking in long, involved, pedantic sentences that sounded as if they had come from books. He tended to interpret words in odd ways. For example, when hearing someone described as independent he thought this meant they always jumped in at the deep end of the swimming pool. He still takes jokes very seriously. He used to ask the same questions over and over again, regardless of the answers he was given. He did not initiate or join in conversations except by repetitive questioning. L. remained placid and obedient throughout his childhood. He rarely initiated any activity, but waited to be told what to do. As a small child he used to rock himself when unoccupied. He had no imaginative play. He went to normal school, but did not join in with the other children and had no friends until he was about 14 years old. Then he did begin to mention one or two companions and referred to them as friends, but has lost touch since. He was bullied at school and remembers it as an unhappy time. L. has always been concerned that his possessions should be orderly and that the daily routine should be followed exactly. He is poor at games needing gross motor skills and at tasks requiring hand-eye co-ordination. His posture and gait are markedly odd. His face has a faintly bewildered expression that rarely changes. He uses large, jerky, inappropriate gestures to accompany speech. The odd impression he conveys is exacerbated by his old-fashioned choice of clothing. L. s memory is excellent and this enabled him to pass exams in subjects that can be learnt by rote. He is a very good chess player and enjoys taking part in matches. He can read well and enjoys books on physics and chemistry, concerning which he has memorised a large number of facts. He is particularly interested in time. He wears two watches, one set at Greenwich Mean Time and one at local time, even when these are the same. His major problem is his social ineptitude. He will, for example, go on talking about his special subjects despite the most obvious signs of boredom in his audience. He makes inappropriate, often quite irrelevant, remarks in company and appears gauche and childish. He is painfully aware of his deficiencies, but is unable to acquire the skills necessary for social interaction. Nevertheless, he is kind and gentle and, if he realises someone is ill or unhappy, he will be most sympathetic and do his best to help. Since leaving school he has been employed as a filing clerk, and lives in a hostel. L. s parents did not seek psychiatric help when he was a child, but he has been in contact with psychiatric services since reaching adolescence. On the first occasion he had become agitated because of worries about sex. On the second, he was anxious and losing sleep because of a minor change in his routine at work. On the third he was admitted as an in-patient following attempted suicide, once again precipitated by the possibility of re-organisation in the office where he works. He tried to drown himself, but failed because he is a good swimmer. He then tried to strangle himself, without success. Commenting on this he said The trouble is I am not a very practical person. At admission he was dishevelled in appearance, deeply distressed and sad. His speech was painfully slow with long pauses between phrases. Its content was coherent, although, in his replies to questions, L. tended to add information that was correct, and related to the subject in hand, but not relevant in the context. For example, when asked about relations with his father L. said My father and I get on well. He is a man who likes gardening. L. blamed himself for all his problems, describing himself as an unpleasant person, whom no one could like and who could not manage his own life. He said he had heard people saying things about him such as L. is stupid, L. is a bad person, L. is a chemistry fanatic. Careful questioning and subsequent observation showed that these were misinterpretations of overheard conversations and never occurred when L. was alone. For the first two admissions, the referring agency diagnosed an anxiety state, and for the third, schizophrenia. The final diagnosis was Asperger syndrome complicated by anxiety and depression (not schizophrenia). L. scored in the average range on the WAIS, his verbal being rather higher than his performance score, mainly because of his large vocabulary. The third case history is that of a boy where abnormality was recognised from infancy. B. H. is aged 10. He was delivered by forceps and had difficulty with breathing and cyanosis after birth, remaining in special care for two weeks. He was a large, placid baby, who would lie without moving for long periods. He was not eager to use gestures, to clap or to wave goodbye. His mother was worried about him from the beginning, partly because of the difficult birth and partly because of his behaviour. His parents were certain that he replied Yes appropriately to questions at 11 months. At around 14 months he began to speak in a fluent, but incomprehensible language of his own. He made no effort to crawl, but one day, aged 17 months, he stood up and walked. He learnt to crawl after this. He retained his own language until aged three years, when he started to copy clearly words he heard, and then went on to develop understandable speech. His comprehension of language has always lagged behind his expression. By the age of four he could read. His parents said they did not teach him - he presumably learnt from the television. At the age of five he had a reading age of nine years, but his comprehension was poor. In his early years, B. remained quiet and passive, showing little emotion of any kind. He seemed to prefer a regular routine, but did not react at all to changes. He was not demanding and gave no trouble. B. did not develop imaginative pretend play at the usual age. At the age of about six years he became fascinated with means of transport, read all about them and learn all the technical terms. He enacts actions involving cars, aeroplanes and so on, but never with other children. He appears clumsy and ill-co-ordinated, has problems with buttons and laces, and is afraid of climbing. B. attends a special school. When first admitted he ignored the other children and carried on with his usual preoccupations. He appeared astounded when the teacher indicated that he should obey her instructions and follow the rest of the class. Gradually he began to fit in and to make active social approaches, though in a naive and inappropriate fashion. He has difficulty in following the rules of any game. He speaks in a pedantic style, in an accent quite unlike that of his local environment. For example, he referred to a hole in his sock as a temporary loss of knitting. Many of his phrases are, like this one, inappropriately adapted quotations from television or books. B. is now aware of and sensitive to other peoples criticism, but appears unable to learn the rules of social interaction. When tested at age seven, he had a word recognition age of 12 years, scored at his age level on performance tasks, but was well below this on tests needing recall and comprehension of language. In the following example of the syndrome, the diagnosis is complicated by a history of illness and psychological stress in early life, and by visual impairment. Miss F. G. is aged 26. Pregnancy and delivery were normal, but F. had a series of illnesses and operations, including a subdural haemorrhage of unknown aetiology and correction of strabismus before the age of three years. She has poor eyesight and has to peer very closely to see, but can read, write and type. F. talked fluently at an early age, and had a large vocabulary. Her parents thought she was developing normally until the operation on her eyes at 2 12 years. Following this she was socially withdrawn for several months. No detailed description could be obtained, but her mother was quite certain that there was a marked change in behaviour. Despite the problems of social interaction, F. s speech remained clear, with good vocabulary and grammar. She always had a remarkable memory for anything she had heard or read, including any statistical information. F. gradually became more friendly and, by about three years of age, she was making social approaches to her parents and others in the family. However, she did not interact much with other children. She copied her mothers activities a little, but did not develop normal pretend play or social play. Her main interests as a young child were drawing and, later on, reading. She also collected costume dolls, which she arranged in rows that must not be disturbed. F. went to a normal comprehensive school. She loved history and geography, and would memorise facts in these subjects with ease, but her teacher reported that she would do no work in any subject that did not interest her, such as mathematics. She was accepted at school but recognised as odd. Her conversation contained many long quotations from books and she also often made irrelevant remarks. F. was never good at practical tasks. Her parents tended to do things for her. They found that, if they asked her to do some task, she would begin, but soon stop and turn to her own preferred activity - usually reading a book. After leaving school she obtained work as a typist. She proved an excellent copy typist and was outstandingly accurate at spelling. She made no friends with the other members of staff. After four years the pressure of work increased. F. became distressed and unable to cope. She left work and has been unemployed for three years. During this time she has been anxious and agitated and unable to do anything on her own. She spends her time reading and amassing facts. She tends to have childish temper tantrums if thwarted in any way. The WAIS showed that F. had a verbal score in the average normal range, but performance was very much lower, being in the mildly retarded range. The verbal skills depended on her good vocabulary. She did poorly on any task where the elements bad to be organised into a coherent whole. This is the history of a young man who showed the features of Asperger syndrome, but who was mentally retarded and did not achieve independence as an adult. Mr J. G. is aged 24 and attends a training centre for mentally retarded adults. J. was a quiet, unresponsive baby. He began to say a few words at the age of two, but did not walk until 212 years old. At first he echoed, used phrases repetitively and had poor pronunciation. He learnt to read at the age of 512 and always did well on reading tests, though his comprehension was poor. He knew many unusual or technical words, such as aeronautical and pterodactyl but would be puzzled by familiar ones such as yesterday. He was not aloof, but gentle and passive, tending to stand and watch other children, wanting to join in but not knowing how. He was very affectionate towards his own family. At age 24 he is still unable to interact socially, though is happy to be a passive member of a group. He is clumsy in gait and posture and slow on tests of manual dexterity. J. s special interests are music and cars. He can recognise any make of car, even if shown only a small part of the whole vehicle. He attended a special school for mentally retarded children. He was described by his teacher as showing no initiative. He was eventually placed in an adult training centre near his home, where he is happily settled. His WAIS score at the age of 17 was on the borderline between mild and severe retardation, with the verbal level being very slightly better than the performance. His reading age was still well in advance of all other skills. The following case history is of a boy who at first was classically autistic and later developed the characteristics of Asperger syndrome. C. B. is aged 13. His mother dates C. s problems from the age of six months when his head was accidentally bruised. From this time he became socially aloof and isolated, and spent most of his time gazing at his hands which he moved in complicated patterns in front of his face. At one year old he began to watch the passing traffic, but still ignored people. He continued to be remote, with poor eye contact, until five years of age. He passed his motor milestones at the usual ages and, as soon as he was physically able, he spent hours running in circles with an object in his hand, and would scream if attempts were made to stop him. At the age of three he began to be able to recognise letters of the alphabet and rapidly acquired skill at drawing. He then drew the salt and pepper pots, correctly copying the names written on them, over and over again. For a time this was his sole activity. Following this he became fascinated with pylons and tall buildings and would stare at them from all angles and draw them. He did not speak till the age of four, then for a long time used single words. After this, he acquired repetitive phrases and reversed pronouns. C. had many stereotyped movements as a young child, including jumping, flapping his arms and moving his hands in circles. After the age of five, C. s speech and social contact markedly improved. He attended a special school until aged 11, where they tolerated a range of bizarre, repetitive routines. At one point, for example, he insisted that all his class and the teacher should wear watches that he had made from plasticine before lessons could begin. Despite all the problems, he proved to have excellent rote memory, absorbed all that he was taught, and could reproduce facts verbatim when asked. C. was transferred to a normal comprehensive school at the age of II - He has good grammar and a large vocabulary, though his speech is naive and immature and mainly concerned with his own special interests. He has learnt not to make embarrassing remarks about other peoples appearances, but still tends to ask repetitive questions. He is not socially withdrawn, but he prefers the company of adults to that of children of his own age, finding it difficult to understand the unwritten rules of social interaction. He said of himself, I am afraid I suffer from bad sportsmanship. He enjoys simple jokes but cannot understand more subtle humour. He is often teased by his classmates. His main interest is in maps and road signs. He has a prodigious memory for routes and can draw them rapidly and accurately. He also makes large, complicated abstract shapes out of any material that comes to hand, and shows much ingenuity in ensuring that they hold together. He has never had pretend play but is deeply attached to his toy panda to which he talks as if it were an adult when he needs comfort. His finger dexterity is good, but he is clumsy and ill-co-ordinated in large movements and therefore is never chosen by the other children for sports and team games. C. is of average intelligence on the WISC, with better verbal than performance skills. He does well on tasks needing rote learning, but his teachers are deeply puzzled and concerned about his poor comprehension of abstract ideas and his social naivety. They find him appealing but sadly vulnerable to the hazards of everyday life. Adams,9P. L.9(1973). Obsessive Children: a Sociopsychiatric Study. Butterworths: London. Asperger, H. (1944). Die aunstisehen Psychopathen im Kindesalter. Archiv fur psychiatrie und Nervenkrankheiten 117,76-136. Asperger, H. (1968). Zur differentialdiagnose des kindlichen Autismus. Acta paedopsychiatrica 35, 136-145. Asperger, H. (1979). Problems of infantile autism. Communication 13, 45-52. Bartak, L. amp Rutter, M. (1976). Differences between mentally retarded and normally intelligent autistic children. Journal of Autism and Childhood Schizophrenia 6, 109-120. Bleuler, E. (1911). Dementia Praecox or the Group of Schizophrenias (trans. J. Zinkin). International University Press: New York, 1950. Bosch, 6. (1962). Infantile Autism (trans. D. Jordan and I. Jordan). Springer-Verlag: New York, 1970. Chick, J. Waterhouse, L. amp Wolff, S. (1979). Psychological construing in schizoid children grown up. British Journal of Psychiatry 135, 425-430. DeMyer, M. (1976). Motor, perceptual-motor and intellectual disabilities of autistic children. In Early Childhood Autism (ed. L. Wing), pp169-196. Pergamon: Oxford. DeMyer, M. (1979). Parents and Children in Autism. Winston: Washington. De Sanctis, S. (1906). Sopra alcune varieta della demenza prococe. Rivista Sperimentale de Freniatria di Medicina Legale 32, 141-165. De Sanctis, 5. (1908). Dementia praecocissima catatonica oder Katatonie des fruheren Kindesalters Folia Neurobiologica 2, 9-12. Earl, C. J.C. (1934). The primitive catatonic psychosis of idiocy. British Journal of Medical Psychology 14, 230-253. Everard, P. (1980). Involuntary Strangers. John Clare Books: London. Hulse, W. C. (1954). Dementia infantilis. Journal of Nervous and Mental Disease 119, 471-477. Isaev, D. N. amp Kagan, V. E. (1974). Autistic syndromes in children and adolescents. Acta paedopsychiatrica 40, 182-190. Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child 2, 217-250. Kretschmer, E. (1925). Physique and Character. Kegan Paul, Trench and Trubner: London. Lovaas, 0.1. Schreibman, L. Koegel, R. amp Rehm, R. (1971). Selective responding by autistic children to multiple sensory input. Journal of Abnormal Psychology 77, 211-222. Luria, A. R. (1965). The Mind of Mnemonist (trans. L. Solotaroff). Jonathan Cape: London. 1969. Mahler, M. S. (1952). On child psychosis and schizophrenia: autistic and symbiotic infantile psychoses. Psychoanalytic Study of the Child 7, 286-305. Mnukhin, S. S. amp Isaev, D. N. (1975). On the organic nature of some forms of schizoid or autistic psychopathy. Journal of Autism and Childhood Schizophrenia 5, 99-108. Ornitz, E. M. amp Ritvo, E. R. (1968). Perceptual inconstancy in early infantile autism. Archives of General Psychiatry 18, 7amp98. Ricks, D. M. amp Wing, L. (1975). Language, communication and the use of symbols in normal and autistic children. Journal of Autism and Childhood Schizophrenia 5, 191-221. Robinson, J. F. amp Vitale, L. J. (1954). Children with circumscribed interest patterns. American Journal of Psychiatry 24, 755-767. Schneider, K. (1971). Klinische Psychopathologie (9th edition). Thieme: Stuttgart. Schopler, E. Andrews, C. E. amp Strupp, K. (1979). Do autistic children come from upper middle class parents Journal of Autism and Developmental Disorders 9, 139-152. Van Krevelen, D. A. (1971). Early infantile autism and autistic psychopathy. Journal of Autism and Childhood Schizophrenia 1, 82-86. Wing, J. K. (1978). Clinical concepts of schizophrenia. In Schizophrenia: Towards a New Synthesis (ed. J. K.Wing), pp 1-30. Academic Press: London, Wing, L. (1976). Diagnosis, clinical description and prognosis. In Early Childhood Autism (ed. L. Wing), pp 15-48. Pergamon: Oxford. Wing, L. (1980). Childhood autism and social class: a question of selection British Journal of Psychiatry 137, 410-417. Wing, L. amp Gould, J. (1979). Severe impairments of social interaction and associated abnormalities in children: epidemiology and classification. Journal of Autism and Developmental Disorders 9, 11-29. Wolff, S. amp Barlow, A. (1979). Schizoid personality in childhood: a comparative study of schizoid, autistic and normal children. Journal of Child Psychology and Psychiatry 20, 29-46. Wolff, S. amp Chick, J. (1980). Schizoid personality in childhood: a controlled follow-up study. Psychological Medicine 10, 85-100. First published in Psychological Medicine. 11, p.115-129 Copyright Holders Note: Permission has been granted to put a copy of this article on this World Wide Web page by Cambridge University Press . It is not for reproduction without permission. A Whitepaper by Nancy J Stark, PhD 2015 Clinical Device Group Inc, all rights reserved. Not everyone agrees that there should be a quality management system for clinical research that is, the organizational structure, procedures, processes and resources needed to implement quality control, quality assurance, and quality improvement for clinical research. They argue that there should be one quality management system for a company, and quality from all the various functions should flow naturally from the one system. I disagree. I see a corporate quality management system as having many sub-systems, one for each critical function. Clinical research is one of those critical functionscorrectly viewed as a type of manufacturing validation processbut requiring its own unique set of procedures, processes, and resources operating under a unique mission statement and set apart from the mainstream of the company because of externally imposed ethical principles. 1. FDA 2. ISO 3. OHRP Clinical investigations are the study of medical devices in human subjects, where the devices are not cleared or approved for commercialization by regulatory authorities. Hence, the devices are called 39investigational39. Clinical research is a broader term, used to encompass clinical investigations, registry studies, IVD studies, feasibility studies on new technologies, or any application of a device or technology that can treat or test a human subject or specimen. A study is a detailed examination and analysis of a subject. 4. dictionary It is not a regulatory word, which makes it useful because it doesn39t imply anything beyond its literal meaning. I use the word study to refer to a clinical project with a beginning, middle, and end regardless of whether the project is a clinical investigation or other clinical research. Crafting a Quality System for Clinical Research I view the clinical research function as a business within itself. Your quotcustomersquot are top management, the product development team, marketing, regulatory, FDA, Notified Bodies, and foreign regulators. Your quotproductsquot are data and reports about data. A quality management system provides the written guidance, how-to instructions, forms, tools, and references to implement clinical research from project initiation to completion and to produce reports that are accurate and give management the information they need to make decisions. You need to know the tasks required to complete a clinical research project, a standard of quality for each task, and a way to measure the quality of each task. The quality management system will lay out the tasks, provide templates and tools for each task, and provide methods for measuring quality as you progress through to project completion. But on a broader scale, you need to understand the contribution the clinical department is expected to make to the company, what projects are under the departments purview, and how the clinical department interacts with other departments within the firm. In other words, what are the clinical department39s vision and mission I find it useful to divide a clinical research quality manual (the manual is a binder which houses the quality system) into sections which mimic the progress of a clinical project:0160016001600160 The Quality System0160016001600160 Prestudy Tasks0160016001600160 Study Tasks0160016001600160 Study Close-out Tasks0160016001600160 Database Design0160016001600160 Data Entry amp Analysis0160016001600160 Other Tasks Glossary Glossary Section One: The Quality System The Quality System section describes the management system itself. Here, policy decisions about the scope of the department39s commitment, responsibility, and authority are set forth. It begins with a series of statements. First is a statement of commitment issued by the chief executive officer. The statement is a promise that the company stands firmly on the side of quality, and is made by the CEO to the employees. The second statement sets forth the vision, mission, and quality for the department. A vision is a dream or imagining of the department39s functionfor example, the function might be to assure that safety, efficacy, and performance claims are supported by adequate human data whenever non-human data are insufficient. A mission is a purpose, a reason for existencefor example, the mission might be to assure all human data are collected in compliance with good clinical practice. Quality is when a thing does what it39s supposed to dofor example, quality data and reports reports about data, should accurately and clearly present the data and should meet the reader39s need for information. An operations statement describing when clinical investigations are required and how they fit into the product development cycle is very useful. I use a cross-sectional flowchart to describe the clinical department39s role in the concept, prototype, prepilot, pilot, and production phases of product development. Importantly, section one includes a procedure for the style of a written procedure, and a procedure for the rules of communication with team members located in different geographic areas. Section Two: Prestudy Tasks Eighty percent of your project budget will be spent on prestudy tasks, eighty percent of the project budget will be spent before the first device is applied to the first subject. It39s really important that upper management understand this. A prestudy process, executed with care, typically requires six to eight months. It hurts to see time and money being spent and no data coming in, but over and over again I have seen studies fail because of poor prestudy work or too aggressive a timeline. There are two ways to set up operating procedures: wide and shallow or deep and narrow . A wide and shallow procedure might group all the prestudy tasks into one procedure with numerous plans, reports, and work products resulting from it. A deep and narrow procedure is focused on one task and results in one work product. For example, there are procedures for writing a protocol, designing consent forms, designing case report forms, addressing adverse events, and every other pre-study task that results in a work product. We39ve identified 26 distinct tasks to be executed in the prestudy phase. The value of a deep and narrow method is that each procedure focuses on a single activity, and the list of procedurestaken togetherprovide a schedule of prestudy activities. Section Three: Study Tasks Everyone is excited when study tasks begin finally you have the first device on the first subject and the prospect of feedback about its performance. The study execution process moves away from the company and takes place primarily at the investigator39s sites. Whether your clinical research associates do the monitoring or if you hire separate employees to do the monitoring, someone will have an active travel load. Don39t skimp on the monitoring process. After spending all that time and money setting up a study, make sure a qualified individual travels regularly to the site to assure the device is used per protocol and that problems are spotted early on and fixed. This is the time when data are created the monitoring process is critical to assuring the data will meet your ultimate goals. The most important study task procedures are monitoring trips and reports, adverse event reporting, shipping logs, and data monitoring committee meetings. We39ve identified nine distinct tasks for the study execution process. Section Four: Close-out Tasks It39s tempting to skip study close-out tasks. Everyone is so tired, the focus has turned to analyzing data, and the sites can take care of themselves, right Almost. Some things really do need oversight: make sure you39ve recovered all the remaining devices, wrap up financial disclosure reports, follow-up on outstanding adverse effects, and complete the study documentation checklist. We39ve identified four distinct close-out tasks. Section Five: Database Design The database is a receptacle for receiving and manipulating data. In very small studies you may be able to use Excel, but for most studies you will use a relational database application such as Microsoft SQL Server. Plan to spend 30-60,000 and six months on database design, even more if you outsource it. Unfortunately, no application comes ready-to-wear, you have to build the database de novo to suit your unique study. The cost of database design depends on how many sites, how much data, and the duration of data storage: 1) if you want the data to be entered by the investigative site as it is collected, each investigative site needs its own logon portal and each portal costs money, 2) the quantity of data that will be stored on the server is the second cost source. You determine the quantity of data by counting the number of fields in each case report form and multiplying by the number of subjects. The more gigabytes of data the higher the cost. 3) the third cost factor is the duration of the study. The longer server space must house your data the more it will cost. Procedures for designing a database include planning the tables and records and how you39ll relate them, what standard reports you want, creating a change log, assembling a data dictionary, and making a user39s manual for the data enterer. We have identified two procedures for database design. Section Six: Data Entry amp Analysis Data may be entered into the database either at the investigative site, at an outsourced data management center, or in-house. The obvious value of having sites enter the data is faster feedback. Don39t expect to save money by having investigative sites enter the data. They know that work has been off-loaded from your firm to theirs, and they expect to be paid market-value for their labor. Entering the data in-house has some special challenges. It means that you take full responsibility for data integrity and Part 11 compliance. Think simple if you are a small firm and want to go this route. Buy a stand-alone computer, keep it off the network, put it in a locked room, and give keys only to the people who have authority to enter data, correct data, and run reports. Management does not get a key. The procedures in this section discuss whohowwhere data will be entered, how data integrity will be verified, how to manage data queries, 39locking39 the database, statistically analyzing the data and writing final reports. We include six separate procedures. Section Seven: Other Tasks This section of the quality manual is a place for housing miscellaneous procedures. We include procedures for using healthy (employee) volunteers, maintaining your own IRB, auditing sites, auditing yourself, and reviewing label copy. Reviewing label copy closes the loop on a clinical investigation. If the purpose of the investigation is to obtain data to support safety, efficacy, and performance then assuring there is data on file for each claim in the labeling brings obvious closure to the project. Section 8: Bibliography The manual itself contains a list of significant references. These references provide the history, background, and necessity for the content of a clinical research quality management system. I also recommend that even small companies set up a library of training and reading materials. Such books and references often provide useful examples of how to approach problems and make unusual protocol designs. Every company uses clinical research terms in a manner unique to them. That39s fine. The definitions provided in US regulations or international standards may certainly be refined to meet your corporate needs. A glossary of how your firm uses these terms is extremely important, however, because you want everyone in the company assigning the same meaning to the words. 1 21 CFR Part 812 Investigational Device Exemptions. 2 ISO 14155 Clinical investigations of medical devices in human subjects - good clinical practice (2011). 3 OHRP - Office of Human Research Protections, hhs. govohrp. 4 Dictionary. A Whitepaper by Charles Hurwitz, PhD, and Nancy J Stark, PhD A number of clients have commented to me this year that Notified Bodies are rejecting their Clinical Evaluation Reports for nonconformance to the formatting rules of MEDDEV 2.7.1 r3. Some companies are undertaking complete rewrites of their existing clinical evaluations, so concerned are they that the reports will be rejected at the next review cycle. The EU intends to change the formatting rules, however my European colleagues inform me the 2009 version of the guideline is still firmly in effect and that changes are likely to come slowly. In this whitepaper we39ll review the format suggested by MEDDEV 2.7.1 r3 and look at some common formatting errors. 1. MEDDEV 2.7.1 rev 3 A Muddled History It was people at the Cochrane Library, the US Agency for Healthcare Research and Quality (AHRQ), and the National Library of Congress who first worked with the problem of how to use the existing literature to evaluate safety, efficacy, or performance of products and procedures. The Global Harmonization Task Force Study Group 5 (now defunct) published a document titled quotClinical Evaluationquot in May of 2007. (You may download a copy for free from CDG39s Vintage Guidances web page.) The Active Implantibles Medical Device Directive of 1990 discussed the essential requirement of clinical evaluations in Annex 7. The Medical Device Directive of 1993 discussed the essential requirement of clinical evaluations in Annex X. But neither directive gave much information about format. Both directives were updated in March 2010 with Directive 200747EC, strengthening the requirement for clinical evaluations and their content, but without much regard to format, saying only that the clinical evaluation shall be documented as a report, regularly updated, and signed appropriately. 2. Directive 200747EC Suggested Format from MEDDEV 2.7.1 r3 (2009) In the year or two following the 2010 revision of the Medical Device Directive many of the Notified Bodies (NB) themselves didn39t know how a clinical evaluation report should be written or what their authority was in terms of reviewing them. Any CER that bore even a vague resemblance to what was described in the Directive was deemed to be acceptable. The variety of formats that have crossed our desks has been remarkable. However as time has passed the NBs have better understood their role in the evaluation process. They have formed their own professional society, the Notified Body Operations Group (NBOG), and have issued best practice guides for their members. With the issuance of a checklist for an audit of a Notified Body39s review process, NBs are being held accountable for their decisions and are refusing to accept reports that do not correspond strictly to the MEDDEV 2.7.1 r3 guideline. 3. NBOG CL 2010-1 Appendix E of the MEDDEV guideline is quota possiblequot format for a clinical evaluation report. This is the format you are expected to follow for compliance. Reviewers work with a checklist at the back of the guideline when reviewing a CER and if a section or item is missing you may get a nonconformity, costing extra weeks of review time and lost sales opportunities. What follows is a review of the recommended format for a CER. 4. MEDDEV 2.7.1 r3 p32 1. General DetailsA Three-Legged Stool Think of the clinical evaluation report as a three-legged stool. One leg is the literature review, a second leg is the assessment of your risk management process, and the third leg is the assessment of any clinical investigations your firm has sponsored. The three quotlegsquot are brought together as attachments to a finalized report, the quotseatquot of the stool. In the opening paragraphs of the seat you must take care to identify exactly what device(s) are covered by the report identifying the devices by proprietary name, any code names assigned during device development (one company used the code name quotKermitquot because they intended to leap over the competition,) and the manufacturer(s) of the device. Your firm should assign (or outsource) a medical writer who will act as project manager for preparing the report, have authority to obtain and inspect all necessary records and reports, and have authority to work with external services as needed. In our experience as consultants, it takes about 140 hours of labor over a three month duration to write a clinical evaluation. 2. Description of the device and its intended application in or on the body Provide a concise physical description of the device, cross referencing to relevant sections of the manufacturers technical information as appropriate. The description should cover information such as: materials, including whether the device incorporates a medicinal substance (already on the market or new), tissues, or blood products the device components, including software and accessories mechanical characteristics and other characteristics, such as sterile vs. non-sterile, radioactive, and the like. You should think like the sales department of a successful department store: quotthere shall be no barriers to customer buying. quot In a CER case, there should be no barriers to the Notified Body quickly understanding your technology. Anticipate the questions a nave reviewer will have and address the questions in the seat of the report. It39s useful to include diagrams, drawings, photographs, comparative tables, lists of animal safety testing, text boxes, and the like. These tools help the reviewer to grasp the essence of your technology without doing a lot of independent research. Don39t forget to state the intended application of the device single use or reusable invasive or non invasive implantable or not duration of use or contact with the body organs, tissues or body fluids contacted by the device is the device used in the home and describe how the device achieves its intended purposes. Sometimes clients forget about the processing aids or biological substances used during the manufacturing process. Metal parts are routinely washed with solvents to remove oily residues, biological products may have their origin from unidentified sources of tissue (fish from the sea.) Sometimes the final processing takes place in the physician39s office or lab. You should be able to demonstrate the absence of any inadvertent residue, or that any such residue does not interfere with safety or performance. 3. Intended therapeutic andor diagnostic indications and claims Devices are physically applied on or in the body for a reason: to treat, mitigate, cure or diagnose. You must clearly state the medical conditions (indications) and discuss the medical background for each condition. Reviewers are not experts in all fields of medicine. Your goal as the medical writer is to remove all barriers to clarity, understanding, and full information. You then identify the target treatment groups and diseases for the medical conditions. Who are the patient groups that will be exposed to the device Let39s say the medical condition is pregnancy. The likely patient group is young, healthy women with no concomitant illnesses or genetic variants. What are the diseases or disease subgroups for the medical conditions Again, suppose the medical condition is pregnancy. You may be targeting pregnant women with diabetes, preeclampsia, or other issues. Finally, list the specific safety or performance claims (intended uses) you will make for the device and defend them. You will have some strategic issues to deal with along the way. For example, do you want to mix device indications and, say, cosmetic indications in the same clinical evaluation Or is it a smarter to submit an evaluation for medical use today and amend it for cosmetic use in the future 4. Context of the evaluation Outline the developmental context for the device. The information should include whether the device is based on a new technology, a new clinical application of an existing technology, or the result of incremental change of an existing technology. The amount of information will differ according to the history of the technology. Where a completely new technology has been developed, this section would need to give an overview of the developmental process and the points in the development cycle at which clinical data have been generated. For example, a manufacturer developed an resorbable container in which a patient39s tissue was held in place until it could take hold and grow, as opposed to being held in place with a sling of sutures. The CER included data about both the resorbable container and preparation of the patient39s tissue. For a long standing technology, a shorter description of the history of the technology (with appropriate references) could be used. For example, the CER for a new wound dressing would not need to trace the history of wound dressings all the way back to the Romans. Clearly state if the clinical data used in the evaluation are for an equivalent device. Identify the equivalent device(s) and provide a justification of the equivalency, cross-referenced to the relevant non-clinical documentation that supports the claim. Not to be confused with substantial equivalence, MEDDEV 2.7.1 r3 equivalence (page 42) means, quot1) Clinically: used for the same clinical condition or purpose, at the same site in the body, in similar population (including age, anatomy, physiology) have similar relevant critical performance according to expected clinical effect for specific intended use, 2) Technically: used under similar conditions of use have similar specifications and properties e. g. tensile strength, viscosity, surface characteristics be of similar design use similar deployment methods (if relevant) have similar principles of operation, 3) Biologically: use same materials in contact with the same human tissues or body fluids. quot State the Essential Requirements relevant to the device in question. In particular, describe any special design features that pose performance or safety concerns, e. g. the presence of medicinal, human or animal components. These features should be identified in the device risk management documentation as requiring assessment from a clinical perspective. Sources of data Outline the considerations used to choose the clinical databases for the evaluation. Usually we see publication sources such as PubMed or MAUDE, but rarely do we see a discussion of why these databases were chosen. Provide an outline of the search and retrieval process for scientific literature, including the actual key words and search strings, and cross-reference these to your standard procedure for searching and reporting the literature (you have one, of course.) 5. Summary of the clinical data and appraisal Provide a tabulation of the clinical data used in the evaluation, categorized according to whether the data address the performance or the safety of the device in question. (Note: many individual data sets will address both safety and performance.) Within each category, order the data according to the importance of their contribution to establishing the safety and performance of the device and in relation to any specific claims about performance or safety. Additionally, provide a brief outline of the data appraisal methods used in the evaluation, including any weighting criteria, and a summary of the key results. Include full citations for literature-based data and the titles and investigation codes (if relevant) of any clinical investigation reports. At CDG, we begin an independent Excel spreadsheet as soon as we start reviewing abstracts. The spreadsheet lists the complete title and citation for the abstract, and a justification if the full article is not reviewed further. The spreadsheet is provided as an attachment to the CER. Cross-reference the entry for each item of data to its location in the manufacturers technical documentation. 6. Data analysis 6.1 Performance Provide a description of the how the literature analysis, or analysis of sponsor-acquired clinical data, was used to assess performance. Identify the datasets that are considered to be the most important in contributing to the demonstration of the overall performance of the device and, where useful, particular performance characteristics. Outline why they are considered to be pivotal datasets and how they demonstrate the performance of the device collectively (e. g. consistency of results, statistical significance, clinically significance of effects.) 6.2 Safety Describe the total experience with the device, including numbers and characteristics of patients exposed to the device and duration of follow-up of device recipients. You might include the number of patient-days of exposure, if some patients are exposed or followed longer than others. You should explain if patients were lost to follow-up. Provide a summary of device-related adverse effects, paying particular attention to serious adverse device effects. Provide specific comment on whether the safety characteristics and intended purpose of the device require training of the end-user. 6.3 Product literature and instructions for use State whether the manufacturers proposed product literature and Instructions for Use (IFU) are consistent with the clinical data. Does the literature cover all the hazards and other clinically relevant information that may impact on the use of the device Implanted or home use devices require special consideration, describe how patients will be educated on the care and use of their device and how they can obtain help or additional information, especially outside of business hours. 7 Conclusions to report Outline clearly the conclusions reached about the safety and performance of the device from the evaluation, with respect to the intended use of the device. State whether the risks identified in the risk management documentation have been addressed by the clinical data. For each proposed clinical indication state whether: the clinical evidence demonstrates conformity with relevant Essential Requirements the performance and safety of the device as claimed have been established and the risks associated with the use of the device are acceptable when weighed against the benefits to the patient A word about risk assessments The contents and process of assessing risk is poorly discussed in the MEDDEV 2.7.1 r3 guideline. Here we discuss the process as it is usually performed at CDG. We begin with examining the Instructions for Use (IFU) and the most current Risk Assessment Report (RAR) per ISO 14971. Do the clinical data reveal any new risks not already discussed If yes, you may need to update the RAR and IFU. 5. ISO 14971 2012 Preparing a spreadsheet listing the clinical benefits and risks is a good strategy for grasping their scope. Describe the nature of each benefit and risk in a column and the anticipated outcome in the next column. Indicate the anticipated frequency of occurrence of each benefit and risk in column three. In column four, identify type of adverse effect likely to occur. Next, indicate if the risk would result in a mild, moderate, or severe adverse effect for example, a headache rarely meets the criteria of serious, yet it could be severe. Sometimes we indicate if the risk is associated with the procedure or the device itself. Finally, indicate how the risks have been mitigated. We are trying to gather together as much information as possible to understand the overall risk of the device. Subjectively, we then compare the benefits and risks to determine if one outweighs the other. A number of factors may come into consideration. For example, let39s say that two patients suffer from spondylolisthesis, a defect in the spine which causes vertebra to slip to one side of the body. Let39s also assume that one patient is in her thirties and the other in her seventies. Knowing that it takes a year to recover from corrective surgery, spinal fusion may make sense for the younger patient for whom pain management over fifty years of remaining life is unreasonable. Spinal fusion may not make sense in the older patient, whose life expectancy is ten more years, and who does not want to spend 10 of their remaining lifetime recovering from surgery. Notified Body Check List After you39ve written the report you should check your work using the Notified Body checklist on page 35 of the MEDDEV guidance. Here you will find a thorough and detailed itemization of the points you should include in the report. If you meet all of the criteria in the checklist, a Notified Body will have little power to reject your evaluation based on format alone. 6 MEDDEV 2.7.1 r3, p 35. References 1 MEDDEV 2.7.1 r3, Clinical Evaluation: A guide for manufacturers and Notified Bodies, 2009. 2 Directive 20074EC, Official Journal of the European Union, L 24721. 3 NBOG CL 2010-1 Checklist for audit of Notified Body39s review of Clinical DataClinical Evaluation. 4 MEDDEV 2.7.1 r3, p32. 5 ISO 14971 Application of Risk Management to Medical Devices, 2012. 6 MEDDEV 2.7.1 r3, p 35. 21 February 2012 What Do Notified Bodies Want A Clinical Device Whitepaper by Nancy J Stark We39ve seen an uptick in requests for clinical evaluations recently, and I thought it would be worthwhile to review the requirements. Where you begin depends on where you are now: 1) writing a clinical evaluation for a new, pre-approval device, or 2) writing a clinical evaluation for a device that is already commercial. In the first case, you are asking the question, quotDo I need new clinical data for certificationquot In the second case, you are bringing your documentation up-to-date. Clinical evaluation reports for pre-certification devices If you39re still in the stage of designing your device, you begin by identifying its intended uses. Then you evaluate the existing clinical data to determine if it is sufficient to support safety and performance per the Essential Requirements of the MDD 1 MDD or AIMD 2 AIMD, or if you need additional clinical data. If additional clinical data are needed you have the choice of revising the intended use or performing a clinical investigation. Once you believe the data are sufficient, you convince top management to grant a CE Mark and sign the Declaration of Conformity to your previously certified quality management system. Finally, you will discover the truth when the Notified Body comes to make an inspection call. Clinical evaluation reports for commercial devices The more common situation is that your device is already on the market in Europe, and the Notified Body has informed you that its clinical evaluation is overdue or needs updating. They may give you a grace period, but you are expected to get busy. You follow the same process of evaluating the existing data to determine if it is sufficient to support safety and performance for the intended uses. Should the report conclude that the existing data are insufficient you are in a difficult situation: you39ll need to suspend sales until additional data are acquired. Because the consequences of determining the data are not sufficient are so financially significant for your firm, and the consequences of determining the data are satisfactory are so financially favorable, it is wise if the report writers are as far removed from the device designers as possible. Resources To write the report you need a team of at least three individuals: 1) a medical writer, 2) an information specialist, and 3) a statistician. In addition you need a written procedure for how to proceed, a report template (useful, but not required), and access to literature databases such as Medline. Medline is easy to use, it is operated by the US National Library of Medicine and is available to anyone with a browser. Medline provides access to 5400 worldwide journals in 39 languages dating from 1947 to the present. And it is free. Date Wheels for Clinical Evaluation Planning A typical clinical evaluation involves the following steps and durations: 1 Identify key questions1 weeks. 2 Identify databases to searchoverlaps. 3 Identify search scope, keywords, search strings1 week. 4 Review abstracts, discard with reasons1 week. 5 Acquire articles2 weeks. 6 Read articles1 week. 7 Weight articles for relevance, discard with reasonsoverlaps. 8 Weight articles for statistical validity1 week. 9 Medical writer summarizes literature2 weeks. 10 Review sponsored clinical trials, if any0-2 weeks. 11 Review risk management system amp complaint file2 weeks. 12 Write final evaluation1 week. Date Wheels are a handy, pocket-sized calendar used by project managers to quickly plan simple schedules. If the clinical evaluation work begins on March 1, you can hope for a final report about three or so months later, or about June 1. Buy them here. A Three-Legged Stool First leg The first leg of a Clinical Evaluation Report is an evaluation of the existing literature data. The Global Harmonization Task Force (GHTF) Study Group 5 document quotClinical Evaluationquot coupled with MEDDEV 2.7.1 Rev 3, which is slightly easier to read, are the guidances that tell us how to do the literature evaluation. Here39s what the medical writerworking together with youwill do: 1 Define the key questions. 2 Identify the databases to search (Medline, Embase, MAUDE, Cochrane). 3 Define scope of search and search strategies using a qualified information specialist. 4 Scan the abstracts to identify articles for review. 5 Acquire full-texts of articles. 6 Weight the articles for technical significance, discard anything with a low weight. 7 Have a statistician weight the articles for statistical significance, discard anything with a low weight. 8 Review only those articles with the highest weightings see averages below. The literature data are evaluated to determine if they support safety and performance of the device for its intended use. I like to prepare a separate literature review and attach it to the main clinical evaluation as an annex. The literature review annex has several required elements including the search strings used by the information specialist, a list of abstracts scanned, the articles reviewed, their weights and justification for those weights, and full-text copies of the articles. Second Leg The second leg of the evaluation is a review any existing clinical investigations that your firm may have sponsored. These data are reviewed separately from the literature because you have closer access to the details. The writer asks questions such as: quotWas the Declaration of Helsinki followedquot or quotWere adverse events resolvedquot If not, those facts are noted in the report but the data are not used. Once the writer is satisfied that ethical and administrative requirements were correct, heshe reviews the study results to see if they support safety and performance of the device for its intended use. I like to prepare a separate sponsored study review and attach it to the main evaluation as an annex. Third leg In the third leg, the medical writer comes to the most sensitive step of all examining the complaint file against the risk management system. They review the file to see if complaint handling, as dictated by the risk management system, supports the safety and performance of the device for its intended use. I like to prepare a separate risk management review and attach it to the main evaluation as an annex. The Clinical Evaluation Finally, the medical writer takes the literature review, sponsored study review, and risk management review altogether and reaches an overall conclusion of whether the existing data support the device39s safety and performance for the intended use, or if additional clinical data are needed newly. You know what happens if new clinical data are needed. The Technical File If the data are sufficient, the clinical evaluation is filed away in the Technical File, a written procedure describing the writer39s strategy is incorporated into your quality management system, and you wait with baited breath until the Notified Body inspector comes. Recently CDG conducted a poll on the average number of articles used in a clinical evaluation. Here are the results. Please add your two cents worth below. How long, how much There are only two questions in top management39s mind: 1) how long will it take, and 2) how much will it cost. The answers are simple: quotIt depends. quot Let39s say you have a very nice ultrasonic toothbrush and you intend to use it for cleaning roadside burnsthe kind of burn you get when your motorcycle crashes and your skin scrapes against the pavement. The toothbrush is used to remove the dirt, grit, and tarmac from the wound. It39s an unusual intended use and raises all kinds of questions about potential damage from the bristles, safety features to prevent over-brushing, effects of ultrasound on open wounds, comparing gum tissue to wound tissue, instructions for use, and so on. A clinical evaluation for cleaning wounds will take longer and cost more than a report for brushing teeth with the same device. CDG can help Clinical Device Group is poised and ready to help you with writing your evaluations. We have medical writers, information specialists, experienced statisticians, a written procedure, a standard template, and a proven process. Clinical evaluations written by our specialists have been reviewed by at least three different Notified Bodies and all have been accepted. We work collaboratively with a point-person on your side so that you are involved in the process every step of the way. References 1 Medical Device Directive 9342EEC. 2 Active Implantable Medical Device Directive 90385EEC. 3 Global Harmonization Task Force, Study Group 5, Clinical Evaluations. ghtf. orgsg5sg5-final. html 4 MEDDEV 2.7.1 rev 3. ec. europa. euenterprisesectorsmedical-devicesfilesmeddev271rev3en. pdf 0160 Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc A Whitepaper by Dr. Nancy J Stark During the course of product development there are three times when you should do a literature evaluation: 1) to justify animal use, 2) to justify a clinical trial design, and 3) to apply for certification and CE Mark or Medicare reimbursement. I39ve written previous whitepapers about doing literature evaluations as a part of clinical evaluations. In this whitepaper I39ll0160do a brief overview and then look at literature evaluations to justify animal use. Three literature evaluations Selective Clinical Evaluations ISO 14155 requires a clinical evaluation to justify the design of a clinical trial. 0. ISO 14155. A European colleague showed me several literature evaluations that were done for this purpose. The most important point I noted was that they focused only on the selected indication being investigated, and resulted in a relatively short, compact literature review utilizing only 5-10 publications. Comprehensive clinical evaluations The literature evaluations intended for certification and CE Mark are supposed to be comprehensive, quotThe clinical evaluation is based on a comprehensive analysis of available pre - and post-market clinical data relevant to the intended use of the device in question. quot 1. MEDDEV Clause 5.5.1. However, CDG has been successful with Notified Bodies by averaging 40 articles per review for Class IIa and IIb devices. The number of articles reviewed depends on the number available, the quality of the articles, the age of the technology, the volume of competition, and other similar factors. I observed one European Class III device that got certification and CE Mark based on a review of only 9 case series and 7 publications. Literature reviews for Medicare reimbursement application should be larger and will be more persuasive if they follow the examples found at ahrq. gov. The Agency for Healthcare Research and Quality (AHRQ) has been publishing technology assessment literature reviews for years. If you look at the technology assessment for negative pressure wound therapy (NPWT) devices, you39ll see that 1078 citations were identified, 288 full-text articles retrieved, and 137 articles reviewed. There were also more than 1400 items submitted for review by independent quotinterested partiesquot. The authors point out that none of the studies compared an NPWT system head-to-head to another system. 2. Negative Pressure. Similarly, AHRQ recently released for comment a comparative effectiveness review of devices used in diagnosing cardiac disease in women, including stress electrocardiography, echocardiography, single proton emission computed tomography, cardiac magnetic resonance, and computed tomography angiography. A total of 7163 citations were identified, 1452 full-text articles retrieved, and 101 articles (98 studies) reviewed. The authors note that none of the studies were randomized controlled trials. 3. Diagnosing CAD. This review is currently open for public comment and device manufacturers should absolutely submit publications and data based on research they have done. In 2010 AHRQ received 500,000,000 from the federal government to prepare comparative effectiveness reviews on a wide variety of products. These reviews will surely affect the availability of new and old technologies to the American patient as Medicare revisits its reimbursement decisions based on these reviews. The message to device manufacturers0160is that we will have to rethink how we design clinical trials and be prepared to submit our own clinical evaluations if we are to obtain reimbursement in the American marketplace. Literature evaluations for biological safety I haven39t yet written about literature evaluations to justify the use of animals for biological safety testing or preclinical animal testing. The beauty is that the way you un-justify the use of animals is by demonstrating the work has already been done and does not bear repeatingsaving you costly resourses and the unnecessary use of animals. Let39s look more closely at literature evaluations to justify (or un-justify) animal tests. How to Write A Clinical EvaluationCD Workshop A new CD workshop is now available on quotHow to Write a Clinical Evaluationquot. This well-researched presentation takes you step-by-step through the complicated process of writing a clinical evaluation by making it organized and understandable. The 100 content slides and supporting handouts explain the logistics of clinical evaluations, how to define objectives and key questions, identify and retrieve abstracts, filter and screen abstracts to identify articles, filter again to zone in on the articles that are applicable, assess and weight the literature, and write the evaluation to address the key questions originally posed. The presentation discusses the three major purposes for evaluations, discusses their regulatory foundation, and proposes a strategy to allow each evaluation to build upon the previous ones. Finally, some average metrics are disclosed. If you want a learning guide to help you write a clinical or literature evaluation, this workshop is the place to turn. A procedure, protocol, and templatemeeting the requirements of MEDDEV 2.7.1 r3are available for a small, additional cost. Click here to purchase or more information. Authoritywho says so Take out your current copy of ISO 10993-1 quotBiological evaluation of medical devicesPart 1: Evaluation and testing within a risk management processquot (2009) and turn to Annex C, quotSuggested procedure for literature review. quot 4. ISO 10993-1. The introduction tells us, quotA review and evaluation of the literature is essential for justification and planning of any biological evaluation of a material or a medical device. The aim of such a review is to determine scientific background for the biological evaluation. It also provides essential information for assessing risksbenefits and achieving the ethical conduct of the planned evaluation as required by ISO 10993-2. NOTE Such a literature review can be helpful to assess whether the relevant data available in the literature are sufficient to demonstrate biological safety of the device in question without the need to generate further data from actual testing or to conclude that the available data are not sufficient. Performing a literature review is a scientific activity that should be done with rigor and objectivity, and should allow verification by third parties. quot Methodology 1 Establish a plan The methodology, taken from Annex C, sounds a lot like the methodology described by GHTF Study Group 5 and MEDDEV 2.7.1 r3. The first step is to establish a plan or protocol for the identification, selection, collation and review of all available studies and data. The plan should be documented in writing and based on recognized practices for the systematic review of the scientific literature. 2 Define objectives or key questions The objectives of the literature evaluation should be clearly defined up-front. Sometimes it is easier to phrase the objectives in the form of key questions, for example, which, if any, animal safety tests from the G95-1 Matrix should be performed 5. FDA BlueBook G95-1. Does the chemical characterization of the materials justify not doing animal safety tests Do literature data satisfactorily explain the negative outcomes of certain animal tests Do literature data justify the design of preclinical animal tests, selection of species, route of exposure, duration of exposure or follow-up, or other design parameters 3 Document sources and selection criteria The next step is to identify the sources of literature and other databases that will be searched. The selection will depend on what information you need. For example, you might need evidence regarding the safety of chemicals such as additives or adulterants, information about chemical properties such as glass transition points or vaporization, data about adverse effects related to the device or technology, published studies about in vivo animal use, or information about 39active water39 concentration. The type of data you need will influence where you look for it. You will probably need to contact suppliers directly (called manual searching) to ask for specific information. For example you might need, say, formulation or processing information that isn39t published. In addition, you39ll need to specify criteria for the data. For example, you might accept data from rodents but not from fish, you might require data from certain bacterial strains, large mammals, or ex vivo studies. You might need data with a certain sensitivity, such as parts per billion rather than parts per million. I find it easier to specify what I need than what I don39t need until I have a feeling for what kind of information is out there. 4 Assessment of documents The documents are then valued in such a way as to group them by low, moderate, and high quality, depending on pre-determined assessment criteria and then the values for each criteria are summed to give the document a weight. It may be that some high quality documents are unfavorable to the objectives, but these documents must be included in the evaluation nonetheless. A 39document39 may be anything from a MAUDE report of an adverse event to a full-text published article to information provided directly by a supplier. Documents might be assigned a value on: 1) the similarity of the device in the document to the device under consideration, based on technology, critical performance, design, and principles of operation 2) the relevance of the particular experimental animals used in the selected studies for the biological evaluation of the device under consideration and 3) conditions of use of the material or device in the selected documents and the intended use of the device in question. Documents might also be valued on, 4) whether the author39s conclusions are substantiated by the data, 5) whether the document reflects the current medical practice and state of the art technology, 6) whether documents are taken from recognized scientific publications and whether or not they have been reported in peer reviewed journals, and 7) the extent to which the data were acquired through established scientific literature. 5 Critical evaluation of the literature Note that valuation means the act of setting the value of something, while evaluation means a diagnosis or diagnostic study based on those values. 6. Dictionary. Applying these definitions to literature reviews, we can say that we assess a document through the process of assigning it a separate value for each of several criteria, we weight the document by adding up the values, and we evaluate the body of documents (the literature) by determining if they address the key questions, placing the most emphasis on the document with the highest weights. The idea is to evaluate high quality data whether or not it is favorable to our technology. The hoped-for outcome is to conclude than no new animal testing is justified, but it may be that we identify that new animal testing is indeed needed. 6 Format and content The literature evaluation itself may follow the standard format and content of other literature reviews. a A short description of the material and device, including its intended use. I like to include the European and US classification, if known. b Discussion of whether or not the literature supports the objectives or key questions. c Evaluation of the hazards, risks, and appropriate safety measures that should be taken by the manufacturer. d Description of the method of document selection, reasons for omitting documents, and methods of weighting documents. e List of documents (full citations) used in the evaluation and appropriate cross-references. f Conclusion with a justification for whether additional animal testing should be performed or is not necessary. The conclusion should include a discussion of probable risks and benefits, considering the 39state of the art39 of the technology. And the conclusion should identify any gaps in evidence regarding safety or performance that should be addressed by future testing. g The printed names, signatures, and responsibilities of the reviewers, and the dates of signature. I recommend attaching a biosketch or curriculum vitae of the reviewers as evidence of their experience. Conclusion Literature evaluations for biocompatibility are used to determine the need for animal biological safety testing or preclinical testing. Documents both favorable and unfavorable to the technology should be reviewed, but only those documents of the greatest assessed value need be evaluated. Naturally, the hoped-for outcome is that no further testing is needed. The more common situation, however, is for the manufacturer to do a bunch of tests and then turn to the literature to defend an unfavorable outcome. While I39m not a proponent of this strategy, it is wiser to turn to the literature to explain an unwanted test result than to do even more animal testing. If you have unfavorable animal test results, find a knowledgable medical device toxicologist to assess what is currently known about your material, technology, or device, and then do whatever testing is still needed. References 0. ISO 14155 quotClinical investigation of medical devices for human subjectsgood clinical practicequot (2011). 1. MEDDEV 2.7.1 r3 quotClinical Evaluation: A guide for manufacturers and Notified Bodies, quot (2009) clause 5.5.1. 2. AHRQ quotNegative Pressure Wound Therapy Devicesquot, 2009, ahrq. govClinictanegpresswtdreferences. htmref65. 3. AHRQ quotComparative Effectiveness of Noninvasive Technologies for the Diagnosis of Coronary Artery Disease in Womenquot, 2011, effectivehealthcare. ahrq. govindex. cfmresearch-available-for-commentcomment-draft-reportspageactiondisplaydraftcommentformamptopicid202ampproductid770ampdocumenttypedraftReport. 4. ISO 10993-1 quotBiological evaluation of medical devicesPart 1: Evaluation and testing within a risk management processquot (2009). 5. FDA BlueBook Memo G95-1, quotUse of International Standard ISO-10993, 39Biological Evaluation of Medical Devices Part 1: Evaluation and Testing39quot (1995). 6. Dictionary, dictionary. referencebrowseevaluation. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc A Few0160Items of Note about0160Device Regulation in the0160European Union Life keeps moving along in Europe in spite of the snow and closed airports. Here are three important medical device regulatory issues you39ll want to address in the new year. 1 No phase in period for ISO 14155 quotClinical investigation of medical devices in human subjectsgood clinical practicesquot If the stars align, Jupiter stays in the heavens, and my cat stops catching birds, ISO 14155 may be published in the first quarter of 2011. But don39t wait around for the big event. Implementation will be immediate and there is no phase in period The convener recommends all sponsors start updating their clinical investigation procedures now. However, updating your procedures is a little bit difficult because the final draft of the standard is not available for purchase on the iso. org website. ISO. org lists the standard as being under publication (stage 60.00) but provides no means to add it to your shopping cart. The same is true for the Association for the Advancement of Medical Instrumentation at aami. org . which has inexplicably truncated the title to quotClinical investigation of medical devices for human subjectsquot and left off the declaration of quotgood clinical practicesquot. AAMI claims identical equivalency to ISO 14155Ed.3 (edition 3), and states the draft is not available 39outside of committee39. CDG can update your clinical procedures to ISOFDIS 14155 Clinical Device Group is a corporate member of AAMI, a member of ISO TC 194, and has access to the final draft versions of ISOFDIS 14155 quotClinical investigation of medical devices for human subjectsgood clinical practicesquot. While we can39t provide you with a copy of the unreleased document, we can review your existing procedures and make recommendations to bring them into conformance. Our style is to work collaboratively with point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5706 or cdgincclinicaldevice . 0160If you don39t work for one of the thirty or so firms who pay corporate dues to AAMI, are members of TC 194, and have access to the final draft standard, you will have to figure out another game plan. You might consider hiring a CRO with access to the final draft to update your procedures for you. 2 MEDDEV 2.73 Serious adverse event reporting under the amended Directives The European Commission published MEDDEV 2.73 quotSerious Adverse Event Reporting under 90385EEC and 9342EECquot in December 2010. Although the guidance is voluntary, you are strongly urged to follow it. The guidance uses the ISOFDIS 14155 definitions of adverse events and effects, and recommends that all serious adverse events (SAEs), device deficiencies that might lead to SAEs, and any new findings regarding existing SAEs, be reported to every National Competent Authority (NCA) in which the investigation is being conducted. Two categories of SAEs The guidance takes the odd approach of dividing SAEs into two categories: a) those that require prompt remedial action, and b) those that do not. SAEs that require prompt remedial action to mitigate an imminent risk of death, serious injury, or serious illness should be reported immediately but no more than 2 (two) calendar days to the NCAs using the Reporting Form provided in the guidance Appendix. SAEs that do not require prompt remedial action should be reported no more than 7 (seven) calendar days. The MEDDEV 2.73 guidance and an Excel spreadsheet of the Reporting Form are provided on CDG39s website. Observations A serious adverse event that occurs at a US site should be reported to every European NCA in which the investigation is also being conducted. CDG recommends that investigations in the US and EU be administered and managed as separate studies because: 1) it is difficult to meet the reporting requirements of two different regulatory entities in the same investigation, and 2) it is difficult to justify pooling data given the differences in medical practice. Patients in countries with socialized medicine tend to be farther along in the disease process before receiving medical care than patients from countries with for-profit medical care. The guidance makes no mention of reporting serious adverse events to Ethical Committees. It doesn39t discuss sharing of data between National Competent Authorities. It doesn39t address setting up a European database of serious adverse events. And it doesn39t address making the SAE reports available to the public. As much as we have complained about a lack of transparency and organization at FDA in recent whitepapers, Europe has a long way to go before it catches up. 3 MEDDEV 2.74 Clinical investigations: A guide for manufacturers and Notified Bodies The European Commission also published MEDDEV 2.74 quotGuidelines on Clinical Investigation: A Guide for Manufacturers and Notified Bodiesquot in December 2010. Again the guideline is not legally binding, but it reflects the thinking of the European Commission and what manufacturers can reasonably expect from their Notified Bodies. Distinctions The guideline tries to clarify the European distinctions between clinical data, clinical evaluation reports, and clinical evidence. The logic is not obvious, so I39ve designed a graphic to help sort it out. Clinical data are numbers, values, measurements, and the like, taken from the literature, sponsored clinical investigations, and other reports such as complaint history files and risk management systems. Clinical data are assessed, analyzed, and written up in clinical evaluation reports. Clinical evidence is both the original clinical data (numbers and values) and the clinical evaluation report. If the clinical evidence is sufficient to establish the safety and performance of a device for its intended use, then the manufacturer may declare conformity to the essential requirements and proceed to market the device. If the clinical evidence is insufficient to establish safety and performance, the manufacturer may withdraw the claim or proceed to a new clinical trial in an effort to generate data to substantiate the claim. Differences between US and EU The fundamentals of good clinical practices haven39t changed and are not much different between the US and EU. The new ISO 14155 standard was written to harmonize as close as possible with the existing ICH-GCPs so if you are an experienced clinical research professional there will be no surprises. But there are some differences in implementation. The first difference is the heavy level of adverse event reporting in Europe. Even for European Class I and IIa devices, all adverse events are reportable to sponsors, Ethics Committees, and NCAs and all serious adverse eventsdevice related or notare reportable to NCAs within 2-7 days. In the States, for significant risk devices, only adverse device effects are reportable to sponsors, IRBs, and FDA (unless FDA requires more for a particular investigation) and for non-significant risk devices, adverse device effects are only reportable to sponsors and IRBs. The second difference will be the increased emphasis on risk management in the clinical investigation process and figuring out how to apply ISO 14971 quotApplication of risk management to medical devicesquot to clinical investigations. Got feedback If you have comments, disagreements, or additional information, please post them below. I look forward to hearing from you. What Do Notified Bodies Want A Whitepaper by Nancy J Stark, PhD. We39ve come a long way in our understanding of what Europe expects in a Clinical Evaluation Report. Where you start depends on where you are: 1) writing a CE Report for a new, pre-approval device, or 2) writing a CE report for a commercial device. In the first case, you are asking the question, quotDo I need new clinical data for certificationquot In the second case, you are bringing your documentation up-to-date. Clinical evaluation reports for pre-certification devices If you39re still in the stage of designing your device, you begin by identifying its intended uses. Then you evaluate the existing clinical data to determine if it is sufficient to support safety and performance per the Essential Requirements of the MDD or AIMD, or if you need additional clinical data. If additional clinical data are needed you have the choice of revising the intended use or performing a clinical trial. Once you believe the data are sufficient, you convince top management to grant a CE Mark and sign the Declaration of Conformity to your quality management system. Finally, you will discover the truth when the Notified Body comes to call. Clinical evaluation reports for commercial devices The more common situation is that your device is already on the market in Europe, and the Notified Body has informed you that its clinical evaluation report was due last March. He will give you a grace period, but you are expected to conform. You follow the same process of evaluating the existing data to determine if it is sufficient to support safety and performance for the intended uses. Should the report conclude that the existing data are insufficient you are in a difficult situation: you39ll need to suspend sales until additional data are acquired. Because the consequences of determining the data are not sufficient are so financially significant for your firm, and the consequences of determining the data are satisfactory are so financially favorable, it is wise if the report writers are as far removed from the device designers as possible. Resources To write the report you need a team of at least three people: 1) a medical writer, 2) an information specialist, and 3) a statistician. In addition you need a written procedure for how to proceed, a report template (useful, but not required), and access to literature databases such as Medline and Embase. Medline is easy, it is operated by the US National Library of Medicine and is available to anyone with a browser. Medline provides access to 5400 worldwide journals in 39 languages dating from 1947 to the present. And it is free. Embase, on the other hand, is not free. It provides access to an additional 2000 European medical journals, and so, is indispensable since you want to sell in Europe. But it is owned by Elsevier Publishing. You should be prepared to pay a hefty access fee (7000 and up per year) or sub-contract the time from a third-party source. A Three-Legged Stool First leg The first leg of a Clinical Evaluation Report is an evaluation of the existing literature data. The Global Harmonization Task Force (GHTF) Study Group 5 document quotClinical Evaluationquot coupled with MEDDEV 2.7.1 Rev 3, which is slightly easier to read, are the guidances that tell us how to do the literature evaluation. Here39s what the medical writerworking together with youwill do: 1 Define the key questions. 2 Identify the databases to search (Medline, Embase, MAUDE, Cochrane). 3 Define scope of search and search strategies using a qualified information specialist. 4 Scan the abstracts to identify articles for review. 5 Acquire full-texts of articles. 6 Weight the articles for technical significance, discard anything with a low weight. 7 Have a statistician weight the articles for statistical significance, discard anything with a low weight. 8 Review only those articles with the highest weightings maybe 5-25 articles per intended use. The literature data are evaluated to determine if they support safety and performance of the device for its intended use. I like to prepare a separate literature review and attach it to the main CE Report as an annex. The literature review annex has several required elements including the search strings used by the information specialist, a list of abstracts scanned, the articles reviewed, their weights and justification for those weights, and full-text copies of the articles. Second Leg The second leg of the CE Report is a review any existing clinical investigation that your firm may have sponsored. These data are reviewed separately from the literature because you have closer access to the details. The writer asks questions such as: quotWas the Declaration of Helsinki followedquot or quotWere adverse events resolvedquot If not, those facts are noted in the report but the data are not used. Once the writer is satisfied that ethical and administrative requirements were correct, heshe reviews the study results to see if they support safety and performance of the device for its intended use. I like to prepare a separate sponsored study review and attach it to the main CE Report as an annex. Third leg In the third leg, the medical writer comes to the most sensitive step of all examining the complaint file against the risk management system. They review the file to see if complaint handling, as dictated by the risk management system, supports the safety and performance of the device for its intended use. I like to prepare a separate risk management review and attach it to the main CE Report as an annex. The CE Report Finally, the medical writer takes the literature review, sponsored study review, and risk management review altogether and reaches an overall conclusion of whether the existing data support the device39s safety and performance for the intended use, or if additional clinical data are needed newly. You know what happens if new clinical data are needed. The Technical File If the data are sufficient, the CE Report is filed away in the Technical File, a written procedure describing the writer39s strategy is incorporated into your quality management system, and you wait with baited breath until the inspector comes. How long, how much There are only two questions in top management39s mind: 1) how long will it take, and 2) how much will it cost. The answers are simple: quotIt depends. quot Let39s say you have a very nice ultrasonic toothbrush and you intend to use it for cleaning roadside burnsthe kind of burn you get when your motorcycle crashes and your skin scrapes against the pavement. The toothbrush is used to remove the dirt, grit, and tarmac from the wound. It39s an unusual intended use and raises all kinds of questions about potential damage from the bristles, safety features to prevent over-brushing, effects of ultrasound on open wounds, comparing gum tissue to wound tissue, instructions for use, and so on. A clinical evaluation report for cleaning wounds will take longer and cost more than a report for brushing teeth with the same device. CDG can help Clinical Device Group is poised and ready to help you with writing your reports. We have medical writers, information specialists, experienced statisticians, access to Embase, a written procedure, a standard template, and a proven process. CE Reports written by our specialists have been reviewed by at least three different Notified Bodies and all have been accepted. We work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Buffet approach But perhaps you39d like to do your own medical writing in order to keep down costs, but don39t have access to an information specialist, an experienced statistician, or Embase. Call us anyway, we like to work flexibly to meet your needs. 16 August 2010 New Rules for International Device Trials A Whitepaper and Workshop by Nancy J Stark, PhD Wednesday, 22 September 2010, 11 AM Central or OnDemand soon after.0160 Sweeping changes to ISO 14155 The international standard for medical device clinical research is about to undergo sweeping changes. The first and most evident change is the change in title the standard is now known as ISOFDIS 14155 quot Clinical investigations of medical devices in human subjectsgood clinical practicesquot. Harmonized with the ICH-GCPs, 39Good clinical practices39 was added to the title to signal to the world the Working Group39s intention that this is now the standard to be followed for international medical device investigations. There are other significant changes as well. The mechanical, physical, and engineering nature of devices are taken into account with the integration of the normative reference ISO 14971 quotApplication of Risk Management to Medical Devicesquot. The contents of Investigator39s Brochures looks like a document that reflects a mechanical device rather than a chemical drug, while the requirements for recording and reporting device deficiencies alongside adverse events complements the essential requirements of the MDD and AIMD. All studies are created equal Possibly the hardest thing for Americans to grasp is that there is no risk-based categorization of clinical trials in the standard. The concept of non-significant risk studies versus significant risk studies does not existall the rules apply equally to all clinical investigations. An international standard written by international experts The new standard was written by a team of experts from the US, Europe, and Japan. The team consisted of industry representatives, consultants, and regulators to assure that it was achievable, consistent with country regulations, and in keeping with accepted ethical and organizational practices. It did not come easily the working group and editing committee met fourteen times, with a dozen or so teleconferences sprinkled in between the meetings. One result is a standard that will be an an economic levelerit will be neither easier nor more difficult to conduct a trial in one country over another. Another result is a standard that will be an ethical levelerit will be neither easier nor more difficult to conduct trials in developing countries than developed countries. Format and approach The Part 1 and Part 2 standards from 2003 are now combined into single, comprehensive, 65-page document. The strategy was to approach clinical investigations from a project management perspective. A look at the layout gives an idea of the breadth and depth of the standard. First, there are four administrative sections: 1 Scope. 2 Normative references. 3 Terms and definitions. 4 Ethical considerations. The scope tells us that quotthe principles. apply to all other clinical investigations. quot The statement has no legal precedence but was clearly important to the Europeans. The scope also makes it clear that the standard does not apply to in vitro diagnostic devices. quotNormativequot is ISO-speak for required. It is the one, small sentence under normative references that elevates ISO 14971 to importance. Being listed as a normative reference means that the sponsor is, de facto, non-compliant with ISO 14155 if they are not compliant with ISO 14971. Scattered throughout the document are the many ways in which Risk Analysis Reports are integrated into clinical investigations. These are followed by three project planning sections: 5 Clinical investigation planning. 6 Clinical investigation conduct. 7 Suspension, termination, and close-out. It is not that there is anything new in the project management sections, but there is so much more detail and instructive language. If you have never done a clinical study before, you will find these sections to be a welcome reference. The need for a Clinical Evaluation Report performed according to the principles of GHTF Study Group 5 to justify the design of the clinical protocol is another example of a requirement included to meet the essential requirements of EU Directive 9342EEC on medical devices (MDD) and EU Directive 90385EEC on active implantable medical devices (AIMD). These are followed by two responsibilities sections: 8 Responsibilities of the sponsor. 9 Responsibilities of the principal investigator. Sponsor and principal investigator responsibilities follow closely with FDA39s new guidance quotInvestigator ResponsibilitiesProtecting the Rights, Safety, and Welfare of Study Subjectsquot and the ICH-GCPs. Principal investigators (aka quotinvestigatorsquot in the States) are still required to sign final reports under ISO, but investigators (aka quotco-investigatorsquot or quotsub-investigatorsquot in the States) are off the hook. While much of the detail is laid out in five annexes: Annex A (normative)Clinical investigation plan. Annex B (normative)Investigator39s Brochure. Annex C (informative)Case report forms. Annex D (informative)Clinical investigation report. Annex E (informative)Essential clinical investigation documents. Annex F (informative)Adverse event classification decision tree. Annexes A and B on Clinical Investigation Plans (i. e. protocols) and Investigator39s Brochures are required for compliance, the remaining annexes are for the reader39s information. They contain extremely valuable information on organizing case report forms, writing a final report, and understanding the relationships between adverse events and effects. Other extensive changes Each section was expanded to include sufficient narrative to teach a new sponsor how to conduct a clinical investigation. This controversial move is meant to educate as well as to set a performance bar. Some notable examples of additions or changes include: 1 Clearer definitions of adverse events, adverse device effects, and unanticipated device effects. 2 A new definition, recording, and reporting requirements for device deficiencies. 3 Requirements for recording and reporting adverse device effects in persons other than subjects. 4 Implied requirement for a clinical research quality management system. 5 Requirement for Risk Analysis Report. 6 Requirement for a Clinical Evaluation Report to justify the study design. 7 Required content for a protocol (clinical investigation plan). 8 Required content for an Investigator39s Brochure. 9 Suggested content and organization for case report forms. 10 Discussion of data monitoring committees. 11 Requirements for document and data control. 12 Requirements for electronic data systems. 13 Auditing recommendations. 14 Procedures for suspension or premature termination of a trial. 15 Procedures for working with vulnerable populations. 17 An extensive list of the documents essential for a clinical trial. 18 Omission of the annex discussing how to do a literature review. 19 And, very importantly, two differing attempts at adverse event classification. The publication plan FDIS stands for 39final draft international standard39. While the document is in the final draft stage it is being translated into French and German. Once this is complete the FDIS will be presented to the ISO members (Standards Bodies from each member country) for a final vote, but the only changes allowed at this stage will be spelling, punctuation, or grammar. After publication by ISO in 2011, each member Standards Body will adopt the standard into its own system so in the US the standard will be re-issued as an ANSI (American National Standards Institute) standard of the same number. Oddly enough, a member Standards Body is free to modify the standard, before issuing it under its own name if it wishes. So buyer beware, the French version may be different from the British version or from the US version If you liked the whitepaper, take the workshop The learning objective of this five-hour workshop is to review the changes from the old, 2003 standards to the new, 2010 FDIS. The recording is available by OnDemand or CD at clinicaldevicemallWorkshops. aspx. You will receive, we will discuss x PowerPoint slides. x A 5 hour presentation. x Hints for writing Clinical Evaluation Reports and their role in clinical investigations. x Hints for writing Risk Analysis Reports and their role in clinical investigations. x The required contents of clinical investigation plans (i. e. protocols). x The required contents of investigator39s brochures. x Steps in planning clinical investigations. x Steps in implementing clinical investigations. x Steps in closing-out clinical investigations. x The monitor39s role in clinical investigations. x Responsibilities of sponsors and investigators. x A 30-minute quiz to reinforce your learning experience. x CEUs and certificate of attendance. Who should attend x Clinical research professionals who estimate study costs. x Project managers who want better planning and reporting from their group. x CROs who want to improve their proposal skills. x Executives who are planning the future of their company. Presenter Dr. Nancy J Stark has been a member of Working Group 4 since 2001 and was an active participant in shaping the coming ISO 14155 standard. She is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at nancystark . System requirements x Personal computer. x Internet Access. x Telephone. Date, time, registration The 5 hour workshop will be presented on Wednesday, 22 September 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group IncA biochemistry analyzer measures the composition of blood, urine and other biofluids. Applications The analysis of these fluids is used to diagnose and follow the development of numerous diseases. Such devices are employed in the study of sodium, potassium, chlorine, calcium and other ions. For example, measuring urinary creatinine can furnish a good indication of kidney function. Technologies These instruments can be fully or semiautomatic. The latter require human intervention for sample and reagent preparation. Certain models can perform immunoanalysis, ELISA and other tests in addition to standard biochemical evaluations. How to choose Choice will depend essentially on the degree of automation taking into account the frequency of use of certain specific reagents. Other important factors include accuracy, the number of analyses per hour and the maximum number of samples the analyzer can handle simultaneously. Subscribe to our newsletter