Uji Klinik KP Blok12

7/21/2019 Uji Klinik KP Blok12

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Clinical TrialUji Klinik

Abraham SimatupangDept. of Pharmacology & Therapeutics

Faculty of Medicine – Uniersitas !risten "ndonesia



Profile

Abraham Simatupang

[email protected]

Clinical Pharmacologist

Faculty of Medicine - UKI

oM ! FK UKI "#$%&'oMKes. ! FK U(M "#$$)'or.med. ! Uni*ersity of +onn, "#$$&'

irector ! Acad. of Physiotherapy "//$-

irector of 0as1 Force for 2I3 4 AIS "//5-//$' 2ead of ept. of Pharmacology "//6- irector of 7esearch 8enter "#$$%-//6' Panitia Penilaian 9bat :adi FK UI "///-

;ational 8ommittee ! Ind. rug 7egulatory"/// -

< M e l a y a n i b u 1

a n d i l a y a n i =



What is ClinicalTrial?

A properly planned and

executed clinical trial is a

powerful experimental

technique for assessingthe effectiveness of an

intervention

Ale#ander Flemming



Types of $linical Trials

%pen trial on'randomi(ed controlled trial

)andomi(ed controlled trial*

An e#periment in +hich sub,ects are

randomly allocated into groups-usually called study and controlgroups- to receie or not to receiean e#perimental preentie or

therapeutic procedure- maneuer- orinterention. The results areassessed by rigorous comparison ofrates of disease- death- recoery- orother appropriate outcome in the

study and control groups-



/0" A1T$

Core Components of Clinical Trials

"nole human sub,ects

Moe for+ard in time

Most hae a comparison $%T)%2

group Must hae method to measure

interention

Focus on un3no+ns* e4ect ofmedication

Must be done before medication is partof standard of care

$onducted early in the deelopment of



%ther important things

1thical issues* )esearch proposalshould pass ")5 or "nstitutional1thical $ommittee 6"1$7

"nformed consent

Data management & security

Statistical analysis

Sponsor 8nding- sponsor reporting

Publication planning



The basics design of )$T

Population

Studypopula'

tion

9roup A

9roup 5

9roup n

9roup A

9roup 5

Sampling

)andomallocation

Screenin

g-"nclusion

&e#clusioncriteria

9roup n

"nterentions & measurement

5linding*%ne/doubl

e'blind



$ross'oer design

Studypopula'

tion

9roup A

9roup 5

9roup A

9roup 5

"nterentions & measurements

:ash'out

:ash'out

Placebo Placebo

e+ drug e+ drug



Adantages of )$T

Allo+s rigorous ealuation of a singleariable 6e.g. e4ect & A1s of drug treatments placebo7

Prospectie design Uses hypotheticodeductie reasoning 6see3s

to falsify- rather than to con8rm- its o+nhypothesis7 ; null hypothesis

Potentially eradicate biases by comparingt+o other+ise identical groups

Allo+s for meta analysis



Disadantages of )$T

1#pensie and time consuming

Many )$Ts are either neer done- areperformed on too fe+ patients- or areunderta3en for too short a period.

Most are funded by large researchbodies ; dictate the research agenda

SU))%9AT1 endpoints are oftenused in preference to $2""$A2outcome measures



Scienti8c Aspects of $linical Trial

Phases of $linical Trial Phase " * First in man safety

Phase "" * First in patient dose-

dosage form

Phase """ * 1<cacy- AD)s

Post mar3eting sureillance or

Phase "0 * 1aluation in the real clinical

setting



Phase " %b,ecties

=. To assess a safe & tolerated dose

>. To see if pharmaco3inetics di4er much fromanimal to man

?. To see if 3inetics sho+ proper absorption-bioaailability

@. To detect e4ects unrelated to the e#pected action

. To detect any predictable to#icity

! "nclusion criteria !. Bealthy olunteers * Uniformity of sub,ects* age-

se#- nutritional status C"nformed consent a must

!. 1#ception* Patients only for to#ic drugs 1gAntiB"0- Anticancer

! 1#clusion criteria !. :omen of child bearing age- children-



Phase " 6contEd7

Methods* ! First in Man * Small number of healthyolunteers

! First in a small group of > to >

! Start +ith a dose of about =/= to =/ tolerated

animal dose ! Slo+ly increase the dose to 8nd a safe tolerated

dose

! "f safe in a larger group of up to about –G

! o blinding ! Performed by clinical pharmacologists

! $entre has emergency care & facility for3inetics study

! Performed in a single centre

! Ta3es ? – H months C GI success rate



Phase ""

First in patient C di4erent from healthy olunteer

1arly phase C> – > patients +ith releantdisease ! Therapeutic bene8ts & AD)s ealuated

! 1stablish a dose range to be used in late phase

! Single blind C%nly patient 3no+s comparison +ithstandard drug

2ate phase C – ! Double blind

! $ompared +ith a placebo or standard drug

%utcomes ! Assesses e<cacy against a de8ned therapeutic

endpoint

! Detailed P.3inetic & P.dynamic data

! 1stablishes a dose & a dosage form for future trials

Ta3es H months to > years C ?I success rate



Phase """ 2arge scale- )andomised- $ontrolled trials

Target population* > – = patients Performed by $linicians in the hospital

Minimises errors of phases " and ""

Methods ! Multicentric 1nsures geographic & ethnic

ariations

! Di4 patient subgroups 1g pediatric- geriatric- renalimpaired

! )andomised allocation of test drug /placebo /standard drug

! Double blinded* ! $ross oer design

! 0igilant recording of all aderse drug reactions

! )igorous statistical ealuation of all clinical data

Ta3es a long time* up to years C>I success



$ross oer design

9roup:ee3 = :ee3> :ee3?

" Standard Placebo Test

"" Placebo Test Standard""" Test Standard Placebo

J A +ash out period of a +ee3bet+een t+o +ee3s of therapy



Phase "0 or Post mar3etingSureillance

o 8#ed duration / patientpopulation

Starts immediately after mar3eting

)eport all AD)s

Belps to detect ! rare AD)s

! Drug interactions

! Also ne+ uses for drugs CSometimes

called Phase 0



The drug KstoryL

Pre'clinicalstudies

$linicalstudies 6"'"""7

)egistration

PMS 6Phase"07ot'approed

+ithdra+al

Mar3eting &

Selling



Bo+ to read medical articles



$%S%)T6$onsolidation for )eporting Trials7

Paper section &

topic

Item Description

TITLE & ABT!ACT = Bo+ participants +ere allocated tointerention 6e.g. randomallocation7- ranoomisedE orrandomly assignedE

I"T!#DUCTI#"5ac3ground >

Scienti8c bac3ground ande#planation of rationale

$ET%#D Participants ?

1ligibility criteria for participants andthe settings and locations +here thedata +ere collected

"nterentions @ Precise details of the interentionsintended for each group and ho+ and+hen they +ere actuallyadministered

%b,ecties Speci8c ob,ecties and hypotheses

%utcomes H $learly de8ned primary and

secondary outcome measures and-



$%S%)T 6continued7Paper section &topic

Item Description

Sample si(e G Bo+ sample si(e +as determinedand- +hen applicable- e#planation ofinterim analyses and stopping rules

)andomi(ation –SeNuence generation

O Method use to generate the randomallocation seNuence - includingdetails of any restriction 6e.g.

bloc3ing- strati8cation7

)andomi(ation –Allocationconcealment

Method used to implement therandom allocation seNuence 6e.g.numbered containers or centraltelephone7- clarifying +hether theseNuence +as concealed untilinterentions +ere assigned

)andomi(ation –"mplementation

= :ho generated the allocationseNuences- +ho enrolledparticipants- and +ho assignedparticipants to the groups

5linding 6mas3ing7 == :hether or not participants- thoseadministerin the interention and




Item Description

Statistical methods => Statistical methods used to comparegroups for primary outcomesQMethods for additional analyses-such as subgroup analyses andad,usted analyses

!EULT

Participant Ro+ =? Flo+ of participants through eachstage 6a diagram is stronglyrecommended7. Speci8cally- for eachgroup report the numbers ofparticipants randomly assigned-

receiing intended treatment-completing the study protocol- andanalysed for the primary outcome.Describe protocol deiations fromstudy as planned- together +ithreasons.

)ecruitment =@ Dates de8ning the periods of




Item Description

umbers analysed =H umber of participants6denominator7 in each groupincluded in each analysis and+hether the analysis +as byintention to treatE. State the resultsin absolute numbers +hen feasible6e.g. =/>- not I7

%utcomes andestimations

=G For each primary and secondaryoutcome- a summary of results foreach group- and the estimated e4ectsi(e and its precision 6e.g. I

con8dence interal7Ancillary analyses =O Address multiplicity by reporting any

other analyses performed- includingsub group analyses and ad,ustedanalyses- indicating those pre'speci8ed and those e#ploratory

Aderse eents = All important aderse eents or side




Item Description

DICUI#"

"nterpretation > "nterpretation of the results- ta3inginto account study hypotheses-sources of potential bias orimprecision and the dangers

associated +ith multiplicity ofanalyses and outcomes.

9enerali(ability >= 9enerali(ability 6e#ternal alidity7 ofthe trial 8ndings

%erall eidence >> 9eneral interpretation of the results

in the conte#t of current eidence

A- Sabin $. Medical statistics at a glance. >=>. :iley'5lac3+ell- :est Susse#



The pyramid of Kpo+erL in1idence 5ase Medicine 615M7

Systematicre

ie+/metaanalysis

!CTs

$ohort studies

$ase series

$ase reports

1ditorials & %pinions

2ab studies & Animal research



2eel of 1idence

2eel "* 1idence obtained from at least one properlydesigned randomi(ed controlled trial.

2eel ""'=* 1idence obtained from +ell'designed controlledtrials +ithout randomi(ation.

2eel ""'>* 1idence obtained from +ell'designed cohort orcase'control analytic studies- preferably from more than onecenter or research group.

2eel ""'?* 1idence obtained from multiple time series +ithor +ithout the interention. Dramatic results in uncontrolled

trials might also be regarded as this type of eidence. 2eel """* %pinions of respected authorities- based on clinical

e#perience- descriptie studies- or reports of e#pertcommittees.

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Uji Klinik KP Blok12