UJI KLINIK HERBAL

Rustamaji Farmakologi dan Terapi Fakultas Kedokteran UGM 2010

LATAR BELAKANG PERLUNYA UJI KLINIK

Indikasi bahan herbal untuk penggunaan di dunia medis memerlukan bukti klinik Pelaksanaan uji klinik pada herbal tetap harus menjunjung tinggi hak manusia selaku subject penelitian dengan memperhatikan aspek

Justice Respect

for persons Beneficience Non-maleficience

PEMBAGIAN UMUM UJI KLINIK

Fase 1 : Penelitian pada sejumlah kecil subyek sehat untuk menilai keamanan dan indikasi Fase 2 : penelitian pada subyek sakit dalam jumlah terbatas untuk menilai keamanan dan indikasi Fase 3 : penelitian pada subyek besar dengan pembanding untuk menilai indikasi dan kemanaan

TUJUAN PENELITIAN HERBAL

Mencari bukti ilmiah

Pengalaman

penggunaan herbal di aspek kemanfaatan klinik dan keamanan Kombinasi baru Bentuk sediaan baru Rute pemberian baru

PERSIAPAN STUDI

Literatur review sebagaia basis ilmiah termasuk di sini adalah hasil hasil penelitian pre klinik (farmakodinamik, farmakokinetik, toksikologi)

Fokus kepada apa yang akan diteliti (tujuan penelitian)

KUALITAS BAHAN UJI

Kualitas bahan uji tergantung kepada preparasi yang dilakukan oleh penyedia bahan Herbal terstandar memungkinkan ekstrapolasi yang lebih baik di populasi dibandingkan yang tidak tersandar

PROTOKOL PENELITIAN
Judul Tujuan penelitian Tinjauan pustaka Metode penelitian

Tipe

penelitian : controlled atau open trial Desain penelitian : paralell, crossover Blinding : single, double Randomisasi (metode dan tatacaranya)

PROTOKOL PENELITIAN

Kriteria subyek
Inklusi

dan eksklusi

Jumlah subyek berdasarkan hasil perhitungan statistik End point terapi atau klinis (dapat mencakup aspek quality of life) Kelompok kontrol atau plasebo tergantung pada tujuan penelitian

PROTOKOL PENELITIAN
Tatacara observasi kondisi klinik Tests laboratorium Jadwal pemberian obat dan monitoringnya Kriteria obat lain yang boleh atau tidak boleh digunakan selama penelitian Prosedur untuk memeastikan identitas subyek (daftar kode subyek, catatan pengobatan, daftar randomisasi, CRF)

PROTOKOL PENELITIAN
Prosedur penyiapan, penyimpanan dan pembukaan kode random Kualifikasi peneliti dan pengalaman peneliti Fasilitas yang tersedia ditempat penelitian Metode analisis statistik Informasi tertulis yang diberikan kepada calon subyek penelitian Ijin penelitian

PROTOKOL PENELITIAN
Dokumen sosialisasi kepada tim peneliti Pengobatan emergensi yang disiapkan Daftar pustaka

BACKGROUND AND OBJECTIVE?

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

DESIGN?
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

Parallel

Cross-over

A
R

B A

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 Pregnancy Complication Risk and/or disease factors Etc

Exclusion criteria:

TREATMENT AND CONTROL ?

Controls:

positive (drug/treatment of choice) Negative (placebo) Generic names and formulation(s) Dosage regimens (dose, frequency, duration)

Definition and description of the study drugs:

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 P2 success rate of treatment 1 (e.g., 95%) 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 0.02 0.05 0.10

17.8 15.8 13.0 10.8

14.9 13.0 10.5 8.6

11.7 10.0 7.9 6.2

6.6 5.4 3.8 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
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. 0 = sama sekali tak terasa
1 = ringan 2 = sedang 3 = berat 4 = sangat berat tak tertahan

Kategorisasi: untuk keberhasilan terapi.

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.

13 BASIC PRINCIPLES OF

GOOD CLINICAL RESEARCH

PRACTICES

Sri Suryawati

PRINCIPLE 1.

Clinical research should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements

PRINCIPLE 2.

Forseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A clinical research should be initiated and continued only if the anticipated benefits justify the risks

PRINCIPLE 3.

The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interest of science and society

PRINCIPLE 4.

The available non-clinical and clinical information on an investigation product should be adequate to support the proposed clinical research

PRINCIPLE 5.

Clinical research should be scientifically sound, and described in clear, detailed protocol

PRINCIPLE 6.

A clinical research should be conducted in compliance with the protocol that has been approved by Ethics Committee

PRINCIPLE 7.

The medical care given to, and medical decision made on behalf of subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist

PRINCIPLE 8.

Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his/er respective tasks

PRINCIPLE 9.

Freely given informed consent should be obtained from every subject prior to clinical participation

PRINCIPLE 10.

All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification

PRINCIPLE 11.

The confidentiality of records that could identify subjects should be protected, respecting the existing regulatory privacy and confidentiality rules

PRINCIPLE 12.

Investigation products should be manufactured, handled, and stored in accordance with GMP. They should be used in accordance with the approved protocol

PRINCIPLE 13.

Systems with procedures that assure the quality of every aspect of the research should be implemented

12 RESPONSIBILITY OF

INVESTIGATORS
IN CLINICAL RESEARCH
SRI SURYAWATI

RESPONSIBILITY 1-5
1. 2.

3.

4.
5.

Adequate and safe medical care during and after the trial (predefined time) Ensuring the unbiased selection of an adequate number of subjects for the study The strict adherence to protocol, unless danger Informing predefined parties about any protocol amendments Providing information to trial subjects and obtaining informed consent

RESPONSIBILITY 6-9
6. 7.

8.

9.

Providing adequate facilities and time for the trial Ensuring that the trial has been accepted by the Ethics Committee, and depending on national regulations, by the Drug Regulatory Authority Notifying promptly the relevant parties about serious adverse events or reactions Accepting monitoring and auditing by the sponsor as well as inspections by the drug regulatory authority

RESPONSIBILITY 10-12
10.

11.

12.

The safe handling of data and pharmaceutical products for the trial Informing relevant parties about the reasons for premature termination of the trial Writing a report after the conclusion of the trial and submitting it to relevant parties

PROTECTION TO PATIENTS
AND THE

ROLE OF ETHICS COMMITTEE

IN CLINICAL RESEARCH
SRI SURYAWATI

GROUPS CONCERNED WITH RESEARCH

Ethics Committees

Sponsors

Patients & healthy volunteers

clinical research
Clinical investigators Drug regulatory authorities

PROTECTION TO THE PATIENTS

A. B.

C.
D.

Declaration of Helsinki Informed consents Ethics Committee Confidentiality

A.DECLARATION OF HELSINKI

The current revision of the Declaration of Helsinki* is the accepted basis for clinical trial ethics, and must be fully followed and respected by all parties involved in the conduct of such trials. Any departures from the Declaration must be justified and stated in the protocol. Independent assurance that subjects are protected can only be provided by an ethics committee and freely obtained informed consent.

*2000

B. ETHICS COMMITTEE

To safeguard the rights, dignity, safety, and well-being of all trial subjects

6 responsibilitie
s

EC-RESPONSIBILITY 1

The ethics committee should be constituted and operated so that its tasks can be executed free from bias and from any influence of those who are conducting the trial.

EC-RESPONSIBILITY 2

The ethics committee should have documented policies and procedures as a basis for its work, which should be available to the public. These should set out the authority under which the committee is established, the number of members elected and their qualifications, a definition of what it will review and its authority to intervene, and maintain records of its activities. The documents should also state how frequently the committee will meet and how it interacts with the investigator and/or sponsor.

EC-RESPONSIBILITY 3

The investigator, or the investigator and the sponsor, must consult the relevant ethics committee(s) regarding the suitability of a proposed clinical trial protocol (including appendices and amendments) and of the methods and materials to be used in obtaining and documenting the informed consent of the subjects.

EC-RESPONSIBILITY 4

The ethics committee has an ongoing responsibility for the ethical conduct of research, and therefore must be informed of all subsequent amendments to the protocol and of any serious adverse events occurring during the trial, or other new information likely to affect the safety of the subjects or the conduct of the trial.
The ethics committee should be asked for its opinion if a re-evaluation of the ethical aspects of the trial appears to be required, or if there is any doubt regarding the importance of a protocol change or new information.

EC-RESPONSIBILITY 5

Subjects must not be entered into the trial until the relevant ethics committee(s) has issued its approval on the procedures. The ethics committee should give its opinion and advice in writing within a reasonable time, clearly identifying the trial protocol, itemizing the documents studied and stating the date of review. A list of those present at the committee meeting, including their professional status, should be attached.

EC-RESPONSIBILITY 6
When reviewing a clinical trial proposal the ethics committee should consider the following:

a) Acceptability of the investigator for the proposed trial b) Suitability of the protocol c) Means by which trial subjects will be recruited, d) Adequacy and completeness of the information, which should be written in a language and at a level of complexity understandable to everyone involved, to be given to the subjects, their relatives, guardians or, if necessary, legal representatives. e) Provision, if any, for compensation or treatment in the case of death or other loss or injury of a subject, if attributable to a clinical trial, and details of any insurance or indemnity f) Appropriateness of the extent and form of payment through which the sponsor will remunerate or compensate the organization(s) and/or investigator(s) conducting the trial, and the trial subjects, as required by local laws and regulations. g) Acceptability of proposed amendments to the protocol that are likely to affect the safety of the subjects or the conduct of the trial

C. INFORMED CONSENT

The principles of informed consent in the current revisions of the Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research Involving Human Subjects should be implemented in each clinical trial.

15 points

INFORMED CONSENT 1

The investigator has the overridding responsibility for obtaining informed consent

INFORMED CONSENT 2

Prior to the beginning of the trial, the investigator should have the Ethics Committees written approval of the written consent form or any other information to trial subjects Any revised written material should similarly receive approval in advance of use

INFORMED CONSENT 3
Information

should be given in a language and at a level of complexity understandable to the subject in both oral and written form whenever possible.
No

subject should be obliged to participate in the trial.

Subjects,

their relatives, guardians or, if necessary, legal representatives must be given ample opportunity to enquire about details of the trial.

INFORMED CONSENT 4

The information must make clear that the trial is a research procedure, that participation is voluntary and that refusal to participate or withdraw from the trial at any stage will not prejudice the subjects care, rights and welfare.
Subjects must be allowed sufficient time, determined by their health condition and/or the illness, to enquire about details of the trial and to decide whether or not they wish to participate.

INFORMED CONSENT 5
The subject must be made aware and consent that personal information may be scrutinized during monitoring, auditing or inspection of the trial by properly authorized persons, the sponsor or relevant authorities, and that participation and personal information in the trial will be treated as confidential and will not be publicly available

INFORMED CONSENT 6
The

subject must have access to information about insurance, if any, and other procedures for compensation and treatment should he or she be injured or disabled by participating in the trial

INFORMED CONSENT 7

A subject consents to participate after a full and comprehensive explanation of the study, this consent should be appropriately recorded.
The explanation should include: - the aim of the study; - the expected benefits for the subjects and/or others; - the possibility of allocation to a reference treatment or placebo; - the risks and inconveniences; and where appropriate, - an explanation of alternative, recognized medical therapy.

INFORMED CONSENT 8

Consent must be documented either by the subjects dated signature or in agreement with local laws and regulations by the signature of an independent witness who records the subjects consent. In either case, the subject must be informed that signature confirms that the consent is based on information which has been given, and that the subject has freely chosen to participate without prejudice to legal and ethical rights, while reserving the right to withdraw from the study at his or her own initiative at any time, without having to give any reason.

If, however, the reason for withdrawal relates to an adverse event(s), the investigator should be informed.

INFORMED CONSENT 9

Careful consideration should be given to ensuring the freedom of consent obtained from members of a group with a hierarchical structure such as medical, pharmacy and nursing students, hospital and laboratory personnel, employees of the pharmaceutical industry, and members of the armed forces. In such cases the willingness to volunteer may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of a retaliatory response from senior members of the hierarchy in case of refusal to participate.

INFORMED CONSENT 10

Other vulnerable groups whose consent also needs special consideration include patients with incurable diseases, people in nursing homes, prisoners or detainees, the unemployed or people on a very low income, patients in emergency departments, some ethnic and racial minority groups, the homeless, nomads and refugees. If such categories are part of the population to be enrolled in a clinical trial, the ethics committee should consider carefully the appropriateness of the informedconsent process.

INFORMED CONSENT 11
If

the subject is incapable of giving personal consent (e.g. in the case of children or adults who are unconscious or suffering from severe mental illness or disability), the inclusion of such patients in a trial may be acceptable provided:
-

it is permitted by local laws and regulations;

the ethics committee is, in principle, in agreement; and

the investigator thinks that participation will promote the welfare and be in the interest of the subject.

The

agreement of a legally acceptable representative that participation will promote the welfare and be in the interest of the subject should also be recorded by a dated signature.
If

the patient is incapable of giving either signed informed consent or witnessed signed verbal consent, this fact must be documented by the investigator, stating the reasons.

INFORMED CONSENT 12

In a non-therapeutic study,
i.e. when there is no direct clinical benefit to the subject, consent must always be given by the subject and documented by his/her signature.

INFORMED CONSENT 13

The trial subjects should be informed that they have access to appropriate (identified) persons to obtain further information and medical advice or escape treatment, if necessary.

INFORMED CONSENT 14

Any information that becomes available during the trial which may be of relevance to the trial subjects must be made known to them by the investigator.

INFORMED CONSENT 15

The subjects should be informed of the circumstances under which the investigator or the sponsor might terminate their participation in the study.

D. CONFIDENTIALITY

The investigator must establish secure safeguards of confidentiality of research data as described in the current revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects

THE RESPONSIBILITY OF

SPONSOR
IN CLINICAL RESEARCH

GROUPS CONCERNED WITH CLINICAL RESEARCH

Ethics Committees

Sponsors

Patients & healthy volunteers

clinical research
Clinical investigators Drug regulatory authorities

RESPONSIBILITY 1-3
1.

2.

3.

Providing the investigation products as well as appropriate information to support their safe use Ensuring that the trial is conducted in accordance with sound scientific principles and GCP standards Ensuring compliance with applicable legal, ethical, and regulatory requirements

RESPONSIBILITY 4-6
4.

5.

6.

Establishing a quality assurance system for the trial operating independently of those conducting the trial Investigating all serious adverse events and report them to the appropriate authorities Providing compensation and indemnity in the event of a trial-related injury or death

ROLE OF

DRUG REGULATORY AUTHORITY

IN CLINICAL RESEARCH
SRI SURYAWATI

GROUPS CONCERNED WITH RESEARCH

Ethics Committees

Sponsors

Patients & healthy volunteers

clinical research
Clinical investigators Drug regulatory authorities

ROLE OF DRA
To

provide the legal framework for drug development:

To protect the safety and rights of the subjects participating in clinical research To ensure that clinical trials are adequately designed to meet scientifically sound objectives

RESPONSIBILITY 1

The DRA should ensure that the protocols for clinical trials are submitted in advance for review and are in accordance with existing national regulations. On the basis of its review of clinical trial protocols and/or reports, the DRA may propose revisions or request additional data on a clinical trial or terminate a trial.

REVIEW OF PROTOCOLS
POINTS TO CONSIDER:
1. 2. 3. 4. 5.

6.
7. 8. 9. 10. 11.

Objectives and justification for the trial Inclusion and exclusion criteria Rationale for choice of primary and secondary endpoints Description of the type/design of study Randomization and blinding procedures Statistical consideration (e.g. sample size) Descriptions of the trial treatments Methods and timing for measuring efficacy and safety parameters Discontinuation criteria and procedures for breaking randomization codes Accountability procedures for trial treatments Recording and reporting adverse events

REASONS FOR REJECTION

Deficiencies in the documentation Insufficient product quality Safety risks Deficiencies in the design of the protocol Unethical trial Promotional exercise

RESPONSIBILITY 2

The DRA should evaluate the adequacy of supervision of the trial by reviewing the monitors reports to the sponsor. In addition, the authority should be able to conduct on-site inspections of the reliability and quality of reported results.

ON-SITE INSPECTIONS

Inspections may be carried out routinely, randomly and/or for specific reasons
A comparison should be made of the procedures and practices of the investigator with those set out in the protocol and reports submitted to the DRA by the investigator or the sponsor The way in which the investigator has custody of the records and the ease of retrieval should be determined Inspections may include data audit

RESPONSIBILITY 3

National regulations should specify the procedures for reporting and handling cases of misconduct discovered in connection with clinical trials.

ADVERSE EVENTS

The regulations must specify the requirements for reporting to the sponsor, ethics review committee and the DRA respectively The minimum requirement should be that all unexpected and serious events are reported without delay to the DRA Such reports should be evaluated immediately and a decision made on the impact of the report(s) for the continued conduct of the trial in question

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