CRITICAL APRAISAL of CLINICAL TRIAL REPORT Department of Pharmacology and Therapy Division Clinical Pharmacokinetics Faculty of Medicine 2017

Level of evidance Meta analysis Randomized controlled trials Case-controll studies Cohort studies Cross-sectional studies Privious review Clinical intervention non randomized

13 questions Background and objective of the study? Design? Patients selection criteria? Treatment and control (comparator)? Sample size? Randomization? Blinding techniques? Compliance to protocol? Assessment of responses? Analysis? Clinical interpretation? Ethics? Conclusion?

Background and objective? Reasons for conducting a study? Objective(s) Usefulness of the study

Design? A B R Objective of a phase 3 clinical trial: to compare >2 drugs or treatments Randomized controlled double-blind parallel design Randomized controlled double-blind cross-over design R B A Parallel Cross-over

Patients selection criteria? Only patients appropriate for the indication are recruited to the study Inclusion criteria: Diagnostic criteria (clinical & laboratoric) Severity of the disease Pool of patients (hospital or community based) Age, sex Exclusion criteria: Pregnancy Complication Risk and/or disease factors Etc

Treatment and control ? Controls: positive (drug/treatment of choice) Negative (placebo) Definition and description of the study drugs: Generic names and formulation(s) Dosage regimens (dose, frequency, duration) Concomitant medication: Medication(s) not allowed during the study: Masking the effect of study drug? Contraindicated?

Sample size Factors to determine the sample size: Sensitivity of the trial: what is the difference of efficacy between treatment? Interindividual variability? Power of statistics P1 x (100-P1) + P2 x (100-P2) N (pergroup) = ----------------------------------- x f (,) (P1-P2)2 P1 success rate of treatment 1 (e.g., 95%) P2 success rate of treatment 2 (e.g., 90%) f(,) see table ( is type I error,  is type II error)

f(,) table   0.05 0.10 0.20 0.50 0.01 17.8 14.9 11.7 6.6 0.02 15.8 13.0 10.0 5.4 0.05 13.0 10.5 7.9 3.8 0.10 10.8 8.6 6.2 2.7

Randomization? Randomization is a must Aim: to avoid bias in selecting patients and choosing treatment for particular patients If randomization is well conducted, the patients characteristics will be equally distributed in each group of treatments

Blinding techniques Aim: to avoid bias in assessing the drug response Single blind: drug identity is not known by patient Double blind: drug identity is not known by patient and investigator assessing the response Triple blind: drug identity is not known by patient, investigator assessing the response, and the person responsible for data analysis

Compliance to protocol? Incompliance of investigators Incompliance of patients Drop out rate? Concomitant medication? Etc

Assessment of responses Valid and relevant criteria Primary parameter(s) Secondary parameter(s) Additional parameter(s) Timepoints for assessments How to minimize inter-investigators variability in assessing responses Blinding

Data in Clinical trials Demography: age, sex, body weight and height, sosio-ecomomic, Co-morbid : other disease in the same time Pre/ko therapy: Other treatment which ricieve before or during study period Data klinis/paraklinis: clinical aspect of disease - problems - subjective clinical judgment - clinical examination - laboratory examination - etc.

SIFAT DATA cara mengukur data subjektif? Data faktual: informasi atas fakta dan peristiwa (umur, tanggal lahir, kematian, penyakit sebelumnya, pengobatan sebelumnya), dll. Data pengukuran objektif: pengukuran klinis (tekanan darah), pengukuran laboratoris (faal hati, tensi, kadar gula darah), dll. Data penilaian subjektif: derajat kecemasan, gejala psikiatrik, penyembuhan, dll. Kesan/pendapat pasien: intensitas nyeri, pengurangan nyeri, kesan hasil pengobatan, dll. cara mengukur data subjektif?

DATA SUBJEKTIF? Scoring: untuk derajat penyakit dan gejala penyakit. Kategorisasi: untuk keberhasilan terapi. 0 = sama sekali tak terasa 1 = ringan 2 = sedang 3 = berat 4 = sangat berat tak tertahan 4 = sangat bagus/sempurna 3 = bagus 2 = sedang/lumaya 1 = sedikit membaik 0 = sama sekali tidak ada perubahan

PENILAIAN & PENGUKURAN Relevan: perjalanan penyakit, efek terapi Handal (reliable): konsisten dan replicable Sensitif: mendeteksi perbedaan kecil Spesifik: - false positif ? - false negatif ? Stabil: perubahan nilai hanya terjadi karena perubahan status penyakit.

RESPONS vs TUJUAN TERAPI Pengobatan profilaksi & prevensi: Pengobatan kausal: Pengobatan simtomatik: Pengobatan paliatif (mengurangi penderitaan dan menunda outcome kematian): Primer: terjadinya penyakit Sekunder: frekuensi kambuh (epilepsi, asma, dll). Proporsi penyembuhan Waktu untuk mencapai kesembuhan Angka komplikasi/kematian Berat ringannya (intensitas) gejala Perbaikan/pengurangan gejala Waktu hilangnya gejala Angka kematian Interval waktu sampai terjadi kematian

WAKTU PENILAIAN RESPONS Sebelum dan sesudah terapi Beberapa kali dalam interval waktu tertentu Kurun waktu tertentu (frekuensi kejadian, frekuensi kumatan, dll) Penilaian dasar Penilaian lanjutan

PENILAI RESPONS Siapa yang menilai? Keragaman antar penilai? Minimisasi variasi/kontrol kualitas penilaian? Penyamaran untuk penilai?

RESPONS? Respons utama: Yang langsung mencerminkan hasil terapi Respons tambahan: Efek terapi tetapi tidak langsung mencerminkan hasil terapi. Efek samping Ketaatan pasien Dll.

Analysis? Appropriate statistical analysis? Appropriate sampel size? ITT vs PP patient populations?

Clinical interpretation? Statistical significance vs clinical significance E.g., 5 mmHg decrease in systolic BP may statistically significant but not clinically significant

Ethical issues? Acceptable reasons to conduct the study Informed consent Ethical clearance

Conclusion? Conclusions should be based on actual findings No place for assumptive, theoretical, or illusive explanations on efficacy

13 questions Background and objective of the study? Design? Patients selection criteria? Treatment and control (comparator)? Sample size? Randomization? Blinding techniques? Compliance to protocol? Assessment of responses? Analysis? Clinical interpretation? Ethics? Conclusion?