Aggiornamento ICH-GCP E6(R2)

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1 Aggiornamento ICH-GCP E6(R2) Cristina Pinasi Independent QA Consultant 13/05/2016

2 Riferimenti legislativi Note for guidance on clinical practice (E6) - CPMP/ICH/135/95, July 1996; (ICH E6) ICH E6 (R 2) Step 2 July 2015 EMA document: 23/July/2015 Step 2b adopted by CHMP for release for consultation Start of public consultation : 04/Aug/2015 End of consultation (public comments): 3 /Feb/2016 (for EU/US) Publication of final guideline: November 2016 It will be a unified standard for EU, Japan, US, Canada and Switzerland to facilitate the mutual acceptance of clinical data by the Regulatory Authorities in these jurisdictions

3 Riferimenti legislativi EMA Reflection paper on risk based quality management in clinical trials EMA/269011/2013 EMA Reflection paper on expectation for electronic source data and data transcribed to electronic data collection tools in clinical trials Aug 2010 EMA draft Reflection paper on GCP compliance in relation to trial master files (paper/electronic) for management, audit and inspection of clinical trials Jun 2015 FDA guidance for Industry Investigator responsibilities Protecting the rights, safety, and welfare of study subjects Oct 2009 FDA final guidance on oversight of clinical investigations a risk-based approach to monitoring Aug 2013 FDA guidance for Industry Electronic source data in clinical investigations Sep 2013 FDA guidance for Industry Computerized systems used in clinical investigations May 2007

4 Scopo della nuova guidance Implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection anda data intergrity. (added in the introduction) Origin Hot topics detected by GCP inspectors in recent years

5 Modifiche principali Source documents requirements ALCOA is mentioned for the first time A definition of quality management that includes efficient protocol design and collection of essential information only Guidance on risk based trial management (including RBM) New emphasis on CSV expectations, as aspects of clinical trials are increasingly computerized Standard regarding electronic records and essential documents have also been updated Additional PI oversight responsibilities

6 Principi delle GCP ICH E6 2.2 Prima che uno studio abbia inizio, devono essere valutati i rischi ed inconvenienti prevedibili rispetto al beneficio atteso I diritti, la sicurezza, e il benessere dei soggetti dello studio costituiscono le considerazioni più importanti e devono prevalere sugli interessi della scienza e della società. 2.5 Gli studi clinici devono essere scientificamente validi, e devono essere descritti in un PROTOCOLLO CHIARO E DETTAGLIATO. 2.6 Lo studio deve essere condotto in conformità al protocollo che abbia preventivamente ricevuto approvazione/parere favorevole di una commissione di revisione dell istituzione (IRB)/un comitato etico indipendente (IEC). 2.8 Tutti gli individui coinvolti nell effettuazione di uno studio devono possedere l istruzione, la preparazione e l esperienza necessarie ad espletare le loro specifiche mansioni.

7 Principi delle GCP ICH E6 2.9 Un consenso informato deve essere ottenuto liberamente fornito da ciascun soggetto prima della sua partecipazione allo studio Ogni informazione relativa allo studio clinico deve essere registrata, trattata e conservata in modo tale da consentire un accurato resoconto, interpretazione e verifica. ADD: questo principio si applica a tutti i record (cartacei o elettronici) 2.11 Deve essere garantita la riservatezza dei documenti che potrebbero identificare i soggetti, rispettando le regole di riservatezza e confidenzialità previste dalle disposizioni normative applicabili I prodotti in sperimentazione devono essere preparati, gestiti e conservati nel rispetto delle Norme di Buona Fabbricazione (GMP) applicabili. Essi devono essere impiegati secondo quanto prescritto dal protocollo approvato Devono essere attuati sistemi e relative procedure che garantiscano la qualità di ogni singolo aspetto dello studio clinico.

8 Investigator s responsibilities Sect. 4.2 Adequate resources demonstation of potential for recruiting the required number of suitable subjects in the agreed recruitment period sufficient time to properly conduct the trial available qualified staff and adequate facilities confirmation that all persons assisting with the trial are adequately informed about the protocol, the IMP, and their trial related duties and functions

9 Investigator s responsibilities NEW The investigator is responsible for supervising any individual or party to whom the Investigator delegates the study tasks conducted at the trial site If the investigator/institution retains the services of any party to perform study tasks they should ensure this party is qualified to perform those study tasks and should implement procedures to ensure the integrity of the study tasks perfomed and any data generated

10 Investigator s responsibilities Già una guidance FDA del 2009 sulle responsabiltà dello sperimentatore aveva proposto un piano in 10 punti per rendere più responsabili i medici sul loro staff, sulla struttura e sulla responsabilità di fornire dati accurati. Anche il nuovo regolamento EU ribadisce lo stesso approccio.. «a PI shall Anche il nuovo regolamento EU ribadisce lo stesso approccio.. «a PI shall assign tasks among the members of the team in a way which is not compromising the safety of subjects and the reliability and robustness of the data generated»

11 Source documents Section 4.9 Records and Reports Lo sperimentatore deve mantenere adequate and accurate SD and trial records that include all pertinent observations on each of the site s trial subjects Source Data are ALCOA (definizione FDA 2007): Accurate Data reflect subject participation Legible Data read without ambiguity Contemporaneous Data written at time of visit Original No copies or re-transcriptions (unless certified copies) Attributable Author clearly identifiable

12 Source documents ICH E6 (R2) Source Data are ALCOAC: Accurate Data reflect subject participation Legible Data read without ambiguity Contemporaneous Data written at time of visit Original No copies or re-transcriptions (unless certified copies) Attributable Author clearly identifiable Complete Manca però il riferimento proposto dalla guidance EMA del 2010 Consistent Enduring Available Sect Se i dati vengono modificati,la modifica deve essere tracciata,non oscurare il dato originale e spiegata se necessaria, anche via audit trail

13 Sponsor Quality Management New Section The largest change to E6 New sponsor responsibility, in detail. Risk assessment and risk mitigation are key topics with all Regulatory Authorities The sponsor should implement a system to manage quality (QMS) throughout the design, conduct, recording, evaluation, reporting of clinical trials. The methods used to assure and control the Quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected Protocols, CRFs, should be clear, concise and consistent. The QMS should use a risk-based approach

14 Sponsor Quality Management Critical processes and data identification to be identified during protocol development Risks identification at system level (facilities, SOP, CS, personnel, vendors) at clinical site level (IMP, trial design, data collection and recording) E6 (R2) proposes a three way risk evaluation methodology: RISK EVALUATION The identified risks should be evaluated considering: The likelihood of errors occuring, given existing risk controls The impact of such errors on human subjects protection and data integrity The extent to which such errors would be detectable

15 Sponsor Quality Management RISK CONTROL The Sponsor should identify those risks that should be reduced (through mitigating actions) and/or can be accepted. Risk mitigation activities may be incorporated in the protocol design, or in the monitoring plans, agreements between parties defining roles and responsibilities (adherence to SOPs, training in processes and SOPs). Predefined quality tolerance limits should be established, taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact the safety or data integrity. Detection of deviations from predefined quality tolerance limits should trigger an evaluation to determine if action is needed. (similar in EMA Risk based quality management)

16 Sponsor Quality Management Risk communication The QM activities should be documented and communicate to stakeholders to faciitate risk review Risk review Risk assessment is not a static event, but should be reviewed to ascertain whether the implemented quality activities remain effective and relevant, taking into account emerging knowledge and experience Risk reporting The QM approach used and important deviations from predefined quality tolerance limits should be reported in the CSR (sect. Data quality assurance) Risk assessment and mitigation plans are required, regardless of whether RBM is being used by the Sponsor.

17 Sponsor oversight of CROs Addenda to sect e Hot topics for Inspectors Sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Sponsor should document approval of any subcontracting of trial-related duties and functions by a CRO. The MHRA GCP Guide (2012) aggiunge: is recommended that the decision to select a particular vendor is documented and rationale is clear; when contracting out monitoring, sponsor must consider how they will maintain oversight of the monitoring team (it is therfore useful to formalized handover procedures; Sponsor should review and approve contracted monitors; all these aspects to be considered in the contract, as well as the process of subcontracting by the vendor)

18 Electronic systems and data handling Addenda to sect /1.60.1/5.5.3 Definition of certified copy A paper or electronic copy of the original record that has been verified ( e.g. by a dated signature) or has been generated through a validated process to produce an exact copy having all of the same attributes and information as the original. In sect. 8.1: when a copy is used to replace an original document, the copy should fulfill the requirements of a certified copy. The EMA Reflection paper of 2010 also had a similar definition of certified copy, which included being able to verify the copy «by a validated electronic process» and EMA also quoted the CDISC clinical research glossary v.8.0 of E6(R2) non specifica però se il processo di verifica tramite la firma datata sia applicabile solo alla singola copia («copy») o anche a un gruppo di documenti

19 Electronic systems and data handling Definition of computer system validation (CSV) A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled. Validation should ensure accuracy, reliability and consistent intended performance, from design until decommissioning of the system or transition to a new system Definition of SOPs needed, as well as training to CS System setup, installation and use System validation and testing Data collection and handling System maintenance System backup and security of access Contingency plans Changes documented (no deletion of entered data, audit trail) Ensure the integrity of data including any data that describe the context, content and structure of data; particularly important in case of software upgrades or migration of data.

20 Risk Based Monitoring (RBM) Sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. flexibility to improve effectiveness and efficiency of monitoring Def Outcome of centralized monitoring should also be reported. The monitoring plan should be tailored to the specific human subject protection and data integrity risks of the trial. New definition for centralized monitoring: remote evaluation of ongoing and/or cumulative data collected from a trial, in a timely manner. Centralized monitoring provides additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring by: Routing review of submitted data Identification of missing data, inconsistencies, protocol deviations, outliers or unexpected lack of variability that may be indicative of systematic or significant errors in data collection at a site, or may be indicative of potential data manipulation or data integrity problems

21 Risk Based Monitoring (RBM) Addenda to sect. 1.39, 5,18.3, e, cont ed Using statistical analyses to identify data trends such as the range and consistency of data within and across sites Analysing site characteristics and performance metrics Selection of sites and/or processes for targeted on-site monitoring Monitoring reports should be provided to Sponsor in a timely manner for review and follow up and they should have sufficient detail to allow verification of compliance with monitoring plan The sponsor should develop a monitoring plan Monitoring stategy / responsibilities of all the parties involved /methods to be used and rationale for their use /critical data and processes to be monitored, particular attention to «non routine practice», requiring training. The plan should reference applicable policies and procedures

22 Serious breaches of GCP Addendum sect When significant noncompliance is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. If required by applicable law, sponsor should inform EC/CA when the noncompliance is a serious breach of the trial protocol or GCP The new future EU Regulation also requires that sponsor reports serious breaches within 7 days of being aware.

23 Sponsor control of investigator data & essential documents Addendum sect. 8.1 Sponsor deve assicurare che lo sperimentatore abbia sempre accesso alle CRF e all audit trail Lo sperimentatore deve avere sotto controllo i documenti e dati prodotti prima/durante/dopo lo studio. Il sistema di archiviazione (irrespective of the media used) deve permettere sicura identificazione dei documenti, la loro ricerca e recupero. La lista alla sez 8 delle GCP è solo una lista di «base» e altri documenti utili per tracciare lo studio possono essere aggiunti e devono essere definiti (ad. es. QP certification, Green light, data base lock certificate )

24 Location of documents Sia per Source documents che essential documents (TMF/ISF) Conservazione Luogo sicuro, accesso limitato (archivio «ongoing»/final) Luogo definito (ICH E6-R2) sect. 8.1 Definizione responsabile del TMF in corso di studio e a fine studio (archivista / PM) Il TMF deve essere «inspection ready» (Dir. 2005/28) per poter dimostrare che lo studio è sotto controllo (in pochi gg deve essere consegnato alle Autorità se richiesto). Se il TMF è elettronico l accesso per gli ispettori deve essere immediato (salvo il tempo per creare l accesso riservato) (EMA Reflection paper on GCP compliance in relation to TMF draft June 2015)

25 GRAZIE per l attenzione! Dott.ssa Cristina Pinasi