Základné dokumenty na vedenie klinického skúšania liekov
Kapitola 8. zo Správnej klinickej praxe vydanej 1.5.1996 Medzinárodnou konferenciou pre harmonizáciu (Smernica ICH E6 (R2), CPMP/ICH/135/95.
Obsah
Text tejto smernice stanovujúcej medzinárodne akceptovateľné požiadavky pre Správnu klinickú prax nenahrádza ale dopĺňa požiadavky právnych predpisov Slovenskej republiky a Európskej únie.
8.1 Úvod
Základné dokumenty sú tie dokumenty, ktoré samostatne a súhrnne dovoľujú hodnotiť priebeh klinického skúšania a kvalitu získaných údajov. Tieto dokumenty preukazujú dodržiavanie štandardov správnej klinickej praxe a platných legislatívnych požiadaviek zo strany skúšajúceho, zadávateľa a monitora. Základné dokumenty plnia aj ďalšie dôležité úlohy. Včasná príprava základných dokumentov u skúšajúceho/v zdravotníckom zariadení a u zadávateľa môže byť nápomocné úspešnému vedeniu skúšania zo strany skúšajúceho, zadávateľa a monitora. Tieto dokumenty sú jedny z tých, ktoré zvyčajne kontroluje nezávislý audit zadávateľa a inšpektujú kontrolné úrady ako súčasť procesu na potvrdenie právoplatného vedenia skúšania a úplnosti zozbieraných údajov.
Nasleduje minimálny zoznam stanovených základných dokumentov. Rôzne druhy dokumentov sú rozdelené do troch častí podľa štádia skúšania, počas ktorého sa obvykle vytvárajú:
1.) pred začatím klinického skúšania,
2.) počas klinického skúšania,
3.) po ukončení a uzatvorení skúšania.
Uvádza sa účel každého dokumentov, ako aj to, či má byť archivovaný u skúšajúceho/v zdravotníckom zariadení, alebo u zadávateľa, alebo u oboch. Zlučovanie niektorých dokumentov je prípustné za predpokladu, že jednotlivé prvky sú jednoducho identifikovateľné. Hlavný súbor skúšania (Trial Master File) má byť vytvorený na začiatku skúšania u skúšajúceho/v zdravotníckom zariadení a v priestoroch zadávateľa. Konečné uzatvorenie skúšania môže prebehnúť iba vtedy, ak monitor skontroluje obe zložky ako u skúšajúceho/zdravotníckom zariadení, tak aj u zadávateľa a potvrdí, že všetky požadované dokumenty sa nachádzajú v príslušných archivačných zložkách. Ktorýkoľvek dokument alebo všetky dokumenty uvedené v tomto usmernení môžu byť predmetom auditu a majú byť k dispozícii pre účely auditu zadávateľa a pre inšpekciu kontrolného úradu (úradov).
Zadávateľ a skúšajúci / zdravotnícke zariadenie by mali uchovávať záznam o umiestnení ich základných dokumentov zahrňujúc zdrojové dokumenty. Systém uchovávania použitý počas klinického skúšania a pre archiváciu (bez ohľadu na použitý typ média) by mal poskytnúť identifikáciu dokumentu, jeho verziu, históriu, vyhľadanie a výber. Kde je to oprávnené (na začiatku klinického skúšania), by sa mali základné dokumenty klinického skúšania doplniť, alebo sa môžu redukovať na základe dôležitosti a relevantnosti špecifických dokumentov klinického skúšania. Zadávateľ má zabezpečiť, aby skúšajúci mal kontrolu a nepretržitý prístup k dátam , ktoré mu zadal cez CRF. Zadávateľ nemá mať výhradnú kontrolu nad týmito údajmi. Keď sa použije kópia nahradzujúca originálny dokument (napr. zdrojové dokumenty, CRF) , kópia by mala spĺňať požiadavky na certifikované kópie. Skúšajúci/ zdravotnícke zariadenie majú mať kontrolu nad všetkými základnými dokumentmi a záznamami, ktoré vytvorili pred, počas a po klinickom skúšaní.
8.2 PRED TÝM, NEŽ SA ZAČNE KLINICKÁ FÁZA SKÚŠANIA
Počas tejto plánovacej fázy sa majú pripraviť tieto dokumenty, ktoré majú byť v spise predtým, než sa skúšanie formálne začne. Uvedený je názov dokumentu v angličtine, jeho význam a umiestnenie v spise u skúšajúceho alebo u zadávateľa.
8.2.1 INVESTIGATOR’S BROCHURE
To document that relevant and current scientific information about the investigational product has been provided to the investigator.
8.2.2 SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)
To document investigator and sponsor agreement to the protocol/amendment(s) and CRF.
8.2.3 INFORMATION GIVEN TO TRIAL SUBJECT
INFORMED CONSENT FORM (including all applicable translations) to document the informed consent.
ANY OTHER WRITTEN INFORMATION to document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consent.
ADVERTISEMENT FOR SUBJECT RECRUITMENT (if used) to document that recruitment measures are appropriate and not coercive (len skúšajúci/zdravotnícke zariadenie.
8.2.4 FINANCIAL ASPECTS OF THE TRIAL
To document the financial agreement between the investigator/institution and the sponsor for the trial.
8.2.5 INSURANCE STATEMENT (where required)
To document that compensation to subject(s) for trial-related injury will be available.
8.2.6 SIGNED AGREEMENT BETWEEN INVOLVED PARTIES, e.g.
- investigator/institution and sponsor
- investigator/institution and CRO
- sponsor and CRO (len zadávateľ)
- investigator/institution and authority(ies) (where required)
8.2.7 DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW
BOARD (IRB) /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
- protocol and any amendments
- CRF (if applicable)
- informed consent form(s)
- any other written information to be provided to the subject(s)
- advertisement for subject recruitment (if used)
- subject compensation (if any)
- any other documents given approval/favourable opinion
To document that the trial has been subject to IRB/IEC review and given approval/favourable opinion. To identify the version number and date of the document(s).
8.2.8 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE COMPOSITION
to document that the IRB/IEC is constituted in agreement with GCP.
8.2.9 REGULATORY AUTHORITY(IES) AUTHORISATION/APPROVAL/NOTIFICATION OF PROTOCOL
(where required) to document appropriate authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable regulatory equirement(s).
8.2.10 CURRICULUM VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS
OF INVESTIGATOR(S) AND SUB-INVESTIGATOR(S) to document qualifications and eligibility to conduct trial and/or provide medical supervision of Subjects.
8.2.11 NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S)
AND/OR TEST(S) INCLUDED IN THE PROTOCOL To document normal values and/or ranges of the tests.
8.2.12 MEDICAL/LABORATORY/TECHNICAL PROCEDURES /TESTS
- certification or
- accreditation or
- established quality control and/or external quality assessment or
- other validation (where required) to document competence of facility to perform required test(s), and support reliability of results.
8.2.13 SAMPLE OF LABEL(S) ATTACHED TO INVESTIGATIONAL PRODUCT CONTAINER(S)
to document compliance with applicable labelling regulations and appropriateness of instructions provided to the subjects (len zadávateľ).
8.2.14 INSTRUCTIONS FOR HANDLING OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
(if not included in protocol or Investigator’s Brochure) to document instructions needed to ensure proper storage, packaging, dispensing and disposition of
investigational products and trial-related materials.
8.2.15 SHIPPING RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
to document shipment dates, batch numbers and method of shipment of investigational product(s) and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability.
8.2.16 CERTIFICATE(S) OF ANALYSIS OF INVESTIGATIONAL PRODUCT(S) SHIPPED
to document identity, purity, and strength of investigational product(s) to be used in the trial (len zadávateľ).
8.2.17 DECODING PROCEDURES FOR BLINDED TRIALS
to document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects' treatment.
8.2.18 MASTER RANDOMISATION LIST
to document method for randomisation of trial population (len zadávateľ)
8.2.19 PRE-TRIAL MONITORING REPORT
to document that the site is suitable for the trial (may be combined with 8.2.20) (len zadávateľ).
8.2.20 TRIAL INITIATION MONITORING REPORT
to document that trial procedures were reviewed with the investigator and the investigator’s trial staff ( may be combined with 8.2.19)
8.3 POČAS VYKONÁVANIA KLINICKÉHO SKÚŠANIA
Okrem dokumentov spisu s vyššie uvedenými dokumentmi. Uvedený je názov dokumentu v angličtine, jeho význam a umiestnenie v spise u skúšajúceho alebo u zadávateľa.
8.3.1 INVESTIGATOR’S BROCHURE UPDATES
to document that investigator is informed in a timely manner of relevant information as it becomes available.
8.3.2 ANY REVISION TO:
- protocol/amendment(s) and CRF
- informed consent form
- any other written information provided to subjects
- advertisement for subject recruitment (if used) to document revisions of these trial related documents that take effect during trial.
8.3.3 DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW
BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
- protocol amendment(s)
- revision(s) of:
- informed consent form
- any other written information to be provided to the subject
- advertisement for subject recruitment (if used)
- any other documents given approval/favourable opinion
- continuing review of trial (where required) to document that the amendment(s) and/or revision(s) have been subject to IRB/IEC review and were given approval/favourable opinion. To identify the version number and date of the document(s).
8.3.4 REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFICATIONS WHERE
REQUIRED FOR:
- protocol amendment(s) and other documents to document compliance with applicableregulatory requirements
8.3.5 CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB-INVESTIGATOR(S) (see 8.2.10)
8.3.6 UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/LABORATORY/ TECHNICAL
PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL to document normal values and ranges that are revised during the trial (see 8.2.11)
8.3.7 UPDATES OF MEDICAL/LABORATORY/TECHNICAL PROCEDURES/TESTS
- certification or
- accreditation or
- established quality control and/or external quality assessment or
- other validation (where required) to document that tests remain adequate throughout the trial period (see 8.2.12)
8.3.8 DOCUMENTATION OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
SHIPMENT (see 8.2.15.)
8.3.9 CERTIFICATE(S) OF ANALYSIS FOR NEW BATCHES OF INVESTIGATIONAL PRODUCTS (see
8.2.16)
(len zadávateľ)
8.3.10 MONITORING VISIT REPORTS
To document site visits by, and findings of, the monitor (len zadávateľ).
8.3.11 RELEVANT COMMUNICATIONS OTHER THAN SITE VISITS
- letters
- meeting notes
- notes of telephone calls to document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) reporting
8.3.12 SIGNED INFORMED CONSENT FORMS
to document that consent is obtained in accordance with GCP and protocol and dated prior to participation of each subject in trial. Also to document direct access permission (see 8.2.3) (len zadávateľ).
8.3.13 SOURCE DOCUMENTS
to document the existence of the subject and substantiate integrity of trial data collected. To nclude original documents related to the trial, to medical treatment, and history of subject (len zadávateľ).
8.3.14 SIGNED, DATED AND COMPLETED CASE REPORT FORMS (CRF)
to document that the investigator or authorised member of the investigator’s staff confirms the observations recorded.
8.3.15 DOCUMENTATION OF CRF CORRECTIONS
to document all changes/additions or corrections made to CRF after initial data were recorded
8.3.16 NOTIFICATION BY ORIGINATING INVESTIGATOR TO SPONSOR OF SERIOUS ADVERSE EVENTS
AND RELATED REPORTS
Notification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11
8.3.17 NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY
AUTHORITY(IES) AND IRB(S)/IEC(S) OF UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
Notification by sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2
8.3.18 NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION
Notification by sponsor to investigators of safety information in accordance with 5.16.2
8.3.19 INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)
Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in accordance with 5.17.3
8.3.20 SUBJECT SCREENING LOG
To document identification of subjects who entered pre-trial screening
8.3.21 SUBJECT IDENTIFICATION CODE LIST
to document that investigator/institution keeps a confidential list of names of all subjects allocatedto trial numbers on enrolling in the trial. Allows
investigator/institution to reveal identity of any subject (len skúšajúci/zdravotnícke zariadenie).
8.3.22 SUBJECT ENROLMENT LOG
To document chronological enrolment of subjects by trial number (len skúšajúci/zdravotnícke zariadenie).
8.3.23 INVESTIGATIONAL PRODUCTS ACCOUNTABILITY AT THE SITE
To document that investigational product(s) have been used according to the protocol.
8.3.24 SIGNATURE SHEET
To document signatures and initials of all persons authorised to make entries and/or corrections on CRFs
8.3.25 RECORD OF RETAINED BODY FLUIDS/TISSUE SAMPLES (IF ANY)
To document location and identification of retained samples if assays need to be repeated.
8.4 PO SKONČENÍ ALEBO ZASTAVENÍ SKÚŠANIA
Uvedený je názov dokumentu v angličtine, jeho význam a umiestnenie v spise u skúšajúceho alebo u zadávateľa.
8.4.1 INVESTIGATIONAL PRODUCT(S) ACCOUNTABILITY AT SITE
To document that the investigational product(s) have been used according to the protocol. To documents the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor.
8.4.2 DOCUMENTATION OF INVESTIGATIONAL PRODUCT DESTRUCTION
To document destruction of unused investigational products by sponsor or at site
8.4.3 COMPLETED SUBJECT IDENTIFICATION CODE LIST
To permit identification of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time (len skúšajúci/zdravotnícke zariadenie).
8.4.4 AUDIT CERTIFICATE (if available)
To document that audit was performed (len zadávateľ).
8.4.5 FINAL TRIAL CLOSE-OUT MONITORING REPORT
To document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate files (len zadávateľ).
8.4.6 TREATMENT ALLOCATION AND DECODING DOCUMENTATION
Returned to sponsor to document any decoding that may have occurred (len zadávateľ).
8.4.7 FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO
THE REGULATORY AUTHORITY(IES) to document completion of the trial (len skúšajúci/zdravotnícke zariadenie).
8.4.8 CLINICAL STUDY REPORT
To document results and interpretation of trial.