CLINICAL TRIAL

Heny EkowatiPharmacy Department

Medicine and Health Sciences FacultyJenderal Soedirman University

Maret 2014

Phase 1 Clinical Trial

These are the earliest trials in the life of a new drug or treatment.

They are usually small trials, recruiting anything up to about 30 patients, although often a lot less.

Phase 1 trials include : 1. The initial introduction of an

investigational new drug into humans; 2. These studies are typically conducted

with healthy volunteers; 3. Sometimes, where the drug is

intended for use in patients with a particular disease, however, such patients may participate as subjects.

Phase 1 trials include :

1. To determine the metabolic and pharmacologic actions of the drug in humans;

2. The side effects associated with increasing doses (to establish a safe dose range), and, if possible,

3. To gain early evidence of effectiveness; they are typically closely monitored.

Phase 1 trials Goal : To obtain sufficient information about the drug's

pharmacokinetics and pharmacological effects to permit the design of well controlled, sufficiently valid Phase 2 studies.

Other examples of Phase 1 studies include studies of drug metabolism, structure-activity relationships, and mechanisms of actions in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.

The total number of subjects involved in Phase 1 investigations is generally in the range of 20-80.

Phase 1 trials :

When laboratory testing shows a new treatment might help treat disease, phase 1 trials are done to find out

1. The safe dose range2. The side effects3. How the body copes with the drug4. If the treatment shrinks cancer

Phase 1 trials : Patients are recruited very slowly onto phase

1 trials. So although they don't recruit many patients, they can take a long time to complete.

The first few patients to take part(called a 'cohort' or group) will be given a very small dose of the drug.

If all goes well, the next group will get a slightly higher dose. The dose will gradually be increased with each group.

Phase 1 trials :

The researchers will monitor the effect, until they find the best dose to give. This is called a 'dose escallation study'.

In a phase 1 trial, you may have lots of blood tests, as the researchers look at how the drug is affecting you. And at how your body copes with, and gets rid of the drug. They will also record any side effects.

Phase 2 Trial

Not all treatments tested in a phase 1 trial make it to a phase 2 trial.

Phase 2 trials are done to find out if the new treatment works well enough to test in a larger phase 3 trial which types of disease the treatment works for

More about side effects and how to manage them

More about the best dose to use

Although these treatments have been tested at phase 1, you may still have side effects that the doctors don't know about. Drugs can affect people in different ways.

Phase 2 trials are often larger than phase 1. There maybe up to 50 or so people taking part. If the results of phase 2 trials show that a new treatment may be as good as existing treatment, or better, it then moves to phase 3.

Phase 2 Trial

Justification for a clinical trial of a conventional drug involves four sets of issues: chemical-manufacturing-control (CMC) issues, non-clinical issues, clinical issues, and ethical issues.

Phase 2 Trial

A Multicenter, Randomized, Controlled Trialof Dexamethasone for Bronchiolitis

NEJM, Juli 2007

We conducted the study in 20 emergency departmentsof the Pediatric Emergency Care Applied Research Network (PECARN) 22 during bronchiolitis season (November through April) from January 2, 2004, through April 30, 2006.

We included infants 2 to 12 months of age to the emergency department with a first episode of bronchiolitis, defined as wheezing (with no prior bronchiolitis, wheezing, or asthma and no bronchodilator use before the current illness), within 7 days after the onset of symptoms. The episode had to be moderate or severe as defined by a score on the Respiratory Distress Assessment Instrument (RDAI)23 of 6 or more (on a scale of 0 to 17, with higher scores indicating more severe respiratory symptoms)(Table 1).

A Multicenter, Randomized, Controlled Trialof Dexamethasone for Bronchiolitis

NEJM, Juli 2007

We excluded infants with a prior adverse reaction to dexamethasone, known heart or lung disease, premature birth (defined as birthbefore 36 weeks of gestation), immunosuppression or immunodeficiency, treatment with corticosteroids in the previous 14 days, active varicella or recent exposure to varicella, or inability of theparent or guardian to speak English or Spanish. Critically ill infants were also excluded.

A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis

NEJM, Juli 2007

Using the same formulation as in prior studies research pharmacies prepared oral dexamethasone solutions (1 mg per milliliter of liquid) from generic dexamethasone phosphate injection solution and identical oral placebo solutions.

The preparations were packaged in identical clear plastic vials labeled only with the randomization numbers. A nurse orally administered 1 ml of solution per kilogram, providing 1 mg of dexamethasone per kilogram in the dexamethasone group (maximum, 12 mg).

A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis

NEJM, Juli 2007

We performed computerized randomization by telephone, using the keypad for data entry. Infants were assigned in equal numbers to the dexamethasone and placebo groups with the use of random permuted blocks stratified by center.

All emergency department staff, study personnel, and parents and guardians were unaware of the group assignments. Randomization codes were secured until all data entry was complete.

A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis

NEJM, Juli 2007

We performed computerized randomization by telephone, using the keypad for data entry. Infants were assigned in equal numbers to the dexamethasone and placebo groups with the use of random permuted blocks stratified by center.

All emergency department staff, study personnel, and parents and guardians were unaware of the group assignments. Randomization codes were secured until all data entry was complete.

A Multicenter, Randomized,

Controlled Trial of Dexamethasone for

BronchiolitisNEJM, Juli 2007

A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis

NEJM, Juli 2007

Assuming a 40% admission rate in the placebogroup, we calculated the sample size that wouldbe required to provide more than 80% power(with a two-sided alpha level of 0.05) to detect aabsolute reduction in hospital admission rates

of 12% or more in the dexamethasone group.

The primary analysis was based on the intention-to-treat principle, with all patients included in their assigned group. A secondary, per-protocol analysis examined the results among infants who actually received the assigned study medication.

Data Analysis

A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis

NEJM, Juli 2007

Hospital admission rates were compared with the use of Pearson’s chi-square test. The RACS was compared in the two groups by means of a two-sample t-test. Adjusted measures and subgroup effects for admission and RACS were analyzed with the use of logistic regression and linear regression, respectively. Generalized estimating equations and linear mixed models were used to test for an interaction between treatment group and site in the admission and RACS outcomes, respectively.

Data Analysis

A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis

NEJM, Juli 2007

Changes in clinical variables after 4 hours of observation were regressed against baseline values and treatment group as predictors. Length-of-stay measures were compared by means of the two-sample Wilcoxon test. The alpha level was set at 0.05 for all analyses, 95% confidence intervals were calculated, and all comparisonswere two-tailed.

Data Analysis

POST MARKETING SURVEILLANCE (PMS)

Pendahuluan

Obat

Efek klinik

Adverse Drug Reactions

Diketahui Tidak diketahui

Insidens: 5%

Pendahuluan Pengembangan obat sangat

pesat Kelemahan antisipasi regulasi Awareness kurang Informasi terlambat Terlanjur dikonsumsi Penetrasi terlalu luas

Kelemahan premarketing trial Jumlah sampel terbatas (< 2000) Waktu singkat (long-term effect ?) Representativeness ? Contoh: ticrynafen, benoxaprofen,

zomepirac, suproven, temafloxacin

BACKGROUND RISK OF DISEASE

Tinggi : 1 per 200/tahun Sedang : 1 per 200 - 10.000/tahun Rendah : 1 per > 10.000/tahun

Jick et al

Metodologi Spontaneous reporting

system Drug-associated event

systems Case control surveillance Outpatient cohort studies

1. Spontaneous reporting system

FDA

Manufactur

Literatur

Adverse event

Report

Jumlah yang terekspos obat (denominator)?Jumlah yang mengalami ADR (numerator) ?Underreporting

Keunggulan Ticrynafen (US, Mei 79 - Mei 80):

hepatocelullar injury (> 500 reports) Benoxaprofen (April 82-Agustus 82): kematian

61 kasus (cholestatic jaundice) di UK (BMJ) Zomepirac (Okt 80-Maret 83): reaksi

anafilaktoid (N Engl J Med 1981): 1100 reports

Suprofen (jan 86-Mei 87): flank pain synd (> 300 reports).

Temafloxacin (US, Feb 1992) anemia hemolitik, disfungsi ginjal, kematian

Keterlambatan: 57 (report)-84 minggu

2. Drug-associated event system

–ethacrynic acid I.v: GI bleeding–heparin flushes: subdural

hematom (neonatal intensive care)

–aspirin: mengurangi risiko infark myokard

1. Intensive hospital-based cohort study

Tujuan: Pola penggunaan obat di RS Detail acute adverse event akibat obat

selama hospitalisasi Patients at risk Frequency major life-threatening events Identifikasi hubungan antara prehospital

drug use & hospital admission

1. Intensive hospital-based cohort study

Prehospital drug exposure

Drug exposure during hospitalisation

Suspected adverse events

Interview

Admission to hospital

Sudden death, jaundice, pulmonary embolism, renal failure, GIHConvulsion, deafnessPsychosis

2. Case-control surveillance

Penggunaan alkohol & Ca. mammae

3. Outpatient cohort studies

NSAID-A

NSAID-B

NO NSAID

Outcome

4. Prescription event monitoring

Structured questionnaire

prescriber

event

Event indikasiumursex concurrent

> 1/1000

Post marketing surveillance

Syarat: Cohort untuk mendeteksi ADR <

1/1000-1/10.000 Control group: non ekspos Control group obat dgn kelas terapi

sama high quality exposure & outcome data biaya: reasonable

Metode PMS

Hypothesis-generating studies Hypothesis-strengthening

studies Hypothesis-testing studies

HYPOTHESIS GENERATING STUDIES

1. Drug specific screening studies

Exposure obat uji

Non exposed group

Exposure obat sejenis

Outcome

HYPOTHESIS GENERATING STUDIES

Matching sex & umur Matching jumlah pasien dengan

obat sejenis Kategori outcome

– dicurigai berkaitan dengan obat berdasarkan studi pada binatang

– biasanya berkaitan dengan obat: alergi, hematologi, hepatotoksik

Contoh: efek teratogenik

Subyek: wanita hamil 2 sub group pembanding, matching:

umur Cohort: infant record, tiap 3 bulan,

selama 1 tahun Outcome:

– penyakit berkaitan dengan yang ditemukan pada uji pra klinik

– penyakit yang sering berkaitan dengan obat (hematologik, neurologik, hepatic, alergik)

– agregat dari birth defect yang memberi kesan efek teratogenik

– penyakit lain selain yang menjadi indikasi obat

2. Disease-specific screening studies

Case-control studies Case: penyakit yang biasa

disebabkan oleh obat 1 kasus: 2 kontrol Pengulangan follow up secara

teratur

HYPOTHESIS GENERATING STUDIES

HYPOTHESIS STRENGTHENING STUDIES

Signals arising elsewhere data pre-marketing data uji klinik data obat lain sejenis

Signals arising from the proposed screening procedures

HYPOTHESIS TESTING STUDIES

Pembanding:– sama sekali tidak terpapar

NSAIDs– terpapar NSAIDs-1– terpapar NSAIDs-2– terpapar NSAIDs-3

Outcome:– kejadian penyakit dlm 30 hr

pasca peresepan & pengamatan

Contoh: NSAIDs

Outcome:–agregat penyakit yang

berkaitan dengan data uji praklinik (GIH, ulkus peptikum, perforasi intestinal, peny. Ginjal)

–penyakit yang berkaitan dengan obat (hepar, eritema, fototoksisitas)

RECORD LINKAGE

Pendahuluan

Pendahuluan

Diet potasium Pencegahan penyakit kardiovaskuler

AINS Efek sampingcardiovaskuler

Antihipertensi Risiko stroke

Masalah

Data agregat, informasi insidentil Comprehensiveness Konsistensi Bias: under/over-estimate Measurement Metodologi sangat ketat

Teknologi

Apotek

Rumah sakit

HEALTH INSURANCE

Metode

Apotek

Rumah sakit

Health insurance

Prasyarat Computerized PIN Universal MIS Confidentiality Fixed population Standard operating procedure Standard diagnosis Standard treatment

Pengukuran Adverse events/suspected

events Drugs dispensed Drugs exposure Temporal sequence Numerator Denominator

Fokus Risk window: interval awal - akhir

pengobatan Periode sebelum & sesudah risk

window Dose-response relationship Membandingkan event rate antara

risk window & pre-post exposure

Dimensi eksposur obat & dampak

Profil pasien: umur, sex, pendidikan, sosioekonomik, compliance

Health status: disease severity Obat: mulai, dosis, jumlah, lama,

frekuensi, concomitant drugs

CHANNELING

Osmotic pump formulation of indomethacin

Pasien dgn riwayatEfek samping GI

channeling

ketoprofen

24,1% denganantiulcer drugs

15,7% dipopulasi

RR=1,54; CI:1,36-1.74

channeling

Beta-2 agonis: salbutamol,terbutalin, fenoterol

Fenoterol + steroid Salbutamol inhalasiHigh risk asthma patient

Glafenin-associated anaphylaxis

Vs. penisilin Vs NSAID’s

RR:16,8, (95%CI:8,5-33,3) RR=32,7; (95%CI:16,9-63)

Pertanyaan: Apa keuntungan dan kelemahan

automated record linkage dari segi:– metodologi– teknis/prosedur– reliabilitas & validitas

Keuntungan Record Linkage

Metodologi -

Teknik – prosedur Mudah Aman

Reliabilitas & validitas Tinggi

Kerugian Record Linkage

Metodologi Terbatas pada daerah tertentu Populasi terbatas

Teknik – prosedur Perlu link dengan sistem komputerisasi mahal

Reliabilitas & validitas -