Jarir Atthobari - Clinical Trial

38
Clinical trial Bagian Farmakologi dan Toksikologi Fak. Kedokteran, Gadjah Mada University

Transcript of Jarir Atthobari - Clinical Trial

Page 1: Jarir Atthobari - Clinical Trial

Clinical trial

Bagian Farmakologi dan ToksikologiFak. Kedokteran, Gadjah Mada University

Page 2: Jarir Atthobari - Clinical Trial

Phase – III Clinical Trial

Randomized Controlled Trial

Ukuran sampel yang besar

Mengevaluasi obat ‘baru’ vs. control (positif/negatif)

Paling mahal dan time consuming

Obat diuji dengan metodologi yang ketat

Page 3: Jarir Atthobari - Clinical Trial

Steps for RCT Design

1. Seleksi subyek penelitian

2. Jenis dan bentuk perlakuan

3. Randomisasi

4. Blinding

5. Pengukuran outcome

6. Analisa data

Page 4: Jarir Atthobari - Clinical Trial

1. Appropriate to the study question2. Generalizable3. Consider the outcome of interest4. Allow adequate recruitment (study

patients you have access to)

Kriteria inklusi

1. Exclude patients with conditions that will compete with the outcomes (e.g. likely early death from cancer)

2. Contradictions to interventions3. Difficult to comply

Kriteria eksklusi

1. Seleksi subyek penelitian

Page 5: Jarir Atthobari - Clinical Trial

• Male and female outpatients• Clinically diagnosed as CAP• Chest-X-ray: pulmonary infiltrate or consolidation• Showing at least three of the following symptom/sign:

– nonproductive cough, – new onset of purulent sputum (productive cough), or– change in the character of their sputum; – sputum culture positive for gram-positive diplococci;– body temperature of 38 7C or more at least twice within a 24 h

period; and/or – elevated leukocyte count (10x10 9 /l).

RCT: azithromycin vs. clarithromycin for adult with mild to moderate CAP

Page 6: Jarir Atthobari - Clinical Trial

Example of exclusion criteria

• Terminal illness• Any condition that could interfere with the attendance

schedule• Patient with the followings:

1. Likely to affect gastrointestinal absorption of antimicrobial activity

2. significant hepatic disease with a serum transaminaselevel more than three times the upper limit of the normal range [serum glutamic oxalacetic transaminase (SGOT) 0.02–0.90 mM/s/; serum glutamic pryruvic transaminase(SGPT) 0.15–0.95 mM/s/l].

3. hypersensitive to azithromycin, clarithromycin, or other macrolide, cyclosporine, theophylline, astemizole, terfenadine, or antacids

Page 7: Jarir Atthobari - Clinical Trial

TreatmentTreatment ControlControl

• Drug formulation • therapeutic class• dosage• drug administration,

frequency• duration of treatment

• standard drug (DOC)• placebo

• non fatal outcome/ disease

Treatment & Control groupTreatment & Control group

2. Jenis dan bentuk perlakuan

Page 8: Jarir Atthobari - Clinical Trial

Sama dalam hal• bentuk• rupa• warna• rasa• bau• konsistensi• cara pemberian

Obat/intervensi

Page 9: Jarir Atthobari - Clinical Trial

RANDOMIZATION

� Objective measures� Equal chance for treatment or control group� Both groups are balanced� To prevent bias

Simple randomization

Randompermuted block

Randompermuted block

within strata

metode

3. Randomize

Page 10: Jarir Atthobari - Clinical Trial

RANDOMIZATION

2 treatment groups: (0-4= A; 5-9=B)

3 treatment groups: (1-3= A; 4-6= B; 7-9 = C)

4 treatment groups (1-2= A; 3-4= B; 5-6= C; 7-9=D)

Simple randomizationSimple randomization

Page 11: Jarir Atthobari - Clinical Trial

128 131 133 142 144 145154 160 162 164 167 181184 188 191 202 203 205216 229 235 237 238 240261 264 272 273 277 278280 281 282 283 289 290291 295 300 312 318 321323 325 327 331 335 338342 349 359 360 366 369372 373 375 384 385 397404 405 414 424 431 436438 446 447 448 458 462469 478 491 498 502 511516 518 520 521 530 535

RANDOM LISTS

Page 12: Jarir Atthobari - Clinical Trial

RANDOMISASI

� 2 treatment groups: AB for 0-4; BA for 5-9

� 3 treatment groups:ABC= 1; ACB= 2; BAC= 3BCA= 4; CAB= 5; CBA= 6

� 2 treatment group with block of 4 patientAABB= 1; ABAB= 2; ABBA= 3BBAA= 4; BABA= 5; BAAB= 6

Random permuted blocksRandom permuted blocks

Page 13: Jarir Atthobari - Clinical Trial

4.BLINDING

� To prevent bias� To prevent prediction effect� Objective measures� Reducing risk of overwhelming

examination

Aims:Aims:

Page 14: Jarir Atthobari - Clinical Trial

RCTs according to whether the investigators and participants know which intervention is being assessed

Open trials

Triple and quadruple-blind trials

Double blind trials

Single blind trials

Page 15: Jarir Atthobari - Clinical Trial

BLINDING

Single blind Double blind Triple blind

Patient Patientdoctor/rater

PatientDoctor/raterStatistician

Page 16: Jarir Atthobari - Clinical Trial

5. PENGUKURAN BASELINE & OUTCOME

� Measurable� Objective� Accurate� Consistent

Page 17: Jarir Atthobari - Clinical Trial

Define potential important variables

Compare between study groups

Account for differences in study design or analysis of results

Measure baseline variables

Page 18: Jarir Atthobari - Clinical Trial

RCT helicobacter pylori eradication in NSAID user

Page 19: Jarir Atthobari - Clinical Trial

Outcome Measures

Easy to diagnose and observeEasy to diagnose and observe

Free of measurement or ascertainment errors

Free of measurement or ascertainment errors

Can be observed independent oftreatment assignment

Can be observed independent oftreatment assignment

Chosen before the start of data collectionChosen before the start of data collection

Clinically relevant Clinically relevant

Page 20: Jarir Atthobari - Clinical Trial

Measurement bias� Measurement error� Recall bias� Observer bias

Page 21: Jarir Atthobari - Clinical Trial

Sumber-sumber bias

� peneliti (misalnya interviewer bias)� subyek penelitian (recall bias)� pengukuran outcome

(measurement bias)

Page 22: Jarir Atthobari - Clinical Trial

� Descriptives

� Survival time: early treatment vs. dead� tumor response: reduction of tumor size

� Duration of treatment vs. treatment response� Patients improvement

� Toxicity

e.g: e.g: cytostaticscytostatics

6. Analisa data

Page 23: Jarir Atthobari - Clinical Trial

Bagaimana menyajikan data descriptive?

Bagaimana menyajikan data descriptive?

�Prosentase�Mean, SD, SEM�Proporsi�RR (relative risk)

Page 24: Jarir Atthobari - Clinical Trial

Bentuk penyajian

0

20

40

60

80

100

1st Qtr 2nd Qtr 3rd Qtr

EastWestNorth

1st Qtr2nd Qtr3rd Qtr4th Qtr

0

20

40

60

80

100

1st Qtr 2nd Qtr 3rd Qtr 4th Qtr

EastWestNorth

Deskripsi0

20

40

60

80

100

120

140

160

180

1st Qtr 2nd Qtr 3rd Qtr 4th Qtr

NorthWestEast

Page 25: Jarir Atthobari - Clinical Trial

Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study

Lancet1998; 352: 1016–21

Page 26: Jarir Atthobari - Clinical Trial

RisikoRisiko relatifrelatif (RR = Relative Risk)(RR = Relative Risk)

PenyakitPenyakit

+ + --

+ a b+ a b

-- c dc dEksposurEksposur

aa------------a + ba + b

RR = RR = ----------------------------cc

------------c + dc + d

RR = (a/RR = (a/a+ba+b) ) –– ((c/c+dc/c+d))

Page 27: Jarir Atthobari - Clinical Trial

Risiko relatif (RR = Relative Risk)

Stroke

+ -

+ 10 90 = 100

- 20 80 = 100BPLD

AR = (a/a+b) – (c/c+d)

Page 28: Jarir Atthobari - Clinical Trial

RR untuk elective SC : 0.24 (95% CI: 0.11 - 0.48)RR untuk non-elective SC : 0.30 (95% CI: 0.25 - 0.35)

Antibiotika profilaksi pada SC mencegah endometritis

95% Confidence interval

Page 29: Jarir Atthobari - Clinical Trial

� RR = 2,45; 95% CI (1,85:2,92)

� RR = 1,85; 95% CI (0,95-2,25)

The estimate of the treatment effect?

95% Confidence interval

Page 30: Jarir Atthobari - Clinical Trial

Risiko Odds (OR = Odds Ratio)

Penyakit

+ -

+ a b

- c dEksposur

a------0 + b

RR = --------------c

------0 + d

OR = ad/bc

Page 31: Jarir Atthobari - Clinical Trial

Relative Risk Reduction

RRR = (|CER – EER|/CER)

CER : Control Event Rate (tanpa terapi dimaksud/plasebo)EER : Experimental Event Rate (dengan terapi dimaksud)

Page 32: Jarir Atthobari - Clinical Trial

The effect of fosinopril on cardiovascular events in population with hypertension

100 patients RCT 50 placebo and 50 fosinoprilAfter 5 years 20 in placebo group and 10 in fosinopril group had CVECER (placebo, %) ?EER (fosinopril, %) ?RRR (CER-EER/CER) ?ARR (|CER-EER|) ?NNT (1/ARR) ?

100 patients RCT 50 placebo and 50 fosinoprilAfter 5 years 20 in placebo group and 10 in fosinopril group had CVECER (placebo, %) ?EER (fosinopril, %) ?RRR (CER-EER/CER) ?ARR (|CER-EER|) ?NNT (1/ARR) ?

CER = control event rateEER = experimental event rateRRR = relative risk reductionARR = absolute risk reductionNNT = number needed to treat

Event rate= cardiovascular events

Page 33: Jarir Atthobari - Clinical Trial

CER (plasebo) 40%EER (fosinopril) 20%CER (plasebo) 40%EER (fosinopril) 20%

Table 5.4 EBM-Sacket

NNT (1/ARR)NNT (1/ARR)

RRR (CER-EER/CER) RRR (CER-EER/CER)

ARR (|CER-EER|) ARR (|CER-EER|)

(40% - 20%)/40% = 50%(40% - 20%)/40% = 50%

40% - 20% = 20 %40% - 20% = 20 %

1/20% = 51/20% = 5

The effect of fosinopril on cardiovascular events in population with hypertension

Page 34: Jarir Atthobari - Clinical Trial

0 1 2 3 4 5 6

Tramadol 75mg

Parasetamol 650 mg

Parasetamol 1000 mg

Aspirin 650 mg

Parasetamol 650 mg + kodein 60 mg

Morfin 10 mg IM

Ibuprofen 400 mg

Ketorolak 10 mg

Naproksen 440 mg

Diklofenak 50 mg

Number Needed to Treat (NNT)

Efikasi berbagai AINS berdasarkan nilaiNNT (Number Needed to Treat)

Page 35: Jarir Atthobari - Clinical Trial

• Confounding occurs when two factors are associated with each other and effect of one is confused with or distorted by the effect of the other

• A confounder is a variable which is associated with the exposure, and independent of that exposure is a risk factor of the disease

ConfoundingConfoundingConfounding

Page 36: Jarir Atthobari - Clinical Trial

To be a confounding factor, two conditions must be met:

Be associated with exposure- without being the consequence of exposure

Be associated with outcome- independently of exposure (not an intermediary)

ConfoundingConfoundingConfounding

Exposure Outcome

Third variable

Page 37: Jarir Atthobari - Clinical Trial

ConfoundingConfounding

Coffee CHD

Smoking

Smoking is correlated with coffee drinking and a risk factor even for those

who do not drink coffee

Page 38: Jarir Atthobari - Clinical Trial

TERIMA KASIH