ASPETTI ETICI ED OPERATIVI OGGETTO DI AUDIT IN UNA SPERIMENTAZIONE IN PAESI IN VIA DI SVILUPPO N.B. Per motivi di riservatezza alcune informazioni sulla sperimentazione non sono riportate Umberto Filibeck UNICRI Progetto Promozione GGPnei PVS Docente Master in sperimentazioni cliniche 1 Università Tor Vergata Roma EU requirements for clinical trials conducted in third countries Directive 2001/83/EC as amended by Directive 2004/27 - Whereas.(13) : ethical requirements of Directive 2001/20/EC to apply to all medicinal products authorised within the community. In particular, with respect to clinical trials conducted outside the Community on medicinal products destined to be authorised within the Community, it should be verified, at the time of the evaluation of the application for authorisation, that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of that Directive. 1
Article 6(1) of Regulation No (EC) 726/2004 and Article 8 (ib) of Directive 2001/83/EC as amended the MAA dossier to contain: A statement to the effect that clinical trials carried out outside the European Union meets the ethical requirements of Directive 2001/20/EC. Section 4 of Introduction to Annex I - Directive 2003/63/EC : applicants shall take into account the scientific guidelines relating to the quality, safety and efficacy of medicinal products for human use Dare effettiva attuazione alla Direttiva 2001/83/CE modificata da Direttiva 2003/63/CE (Codice Comunitario sui medicinali)- Recepimento D.L.vo 219/2006 Le sperimentazioni cliniche eseguite fuori dalla Comunità europea concernenti medicinali destinati ad essere utilizzati nella Comunità europea devono essere predisposte, attuate e descritte secondo la buona pratica clinica ed i principi etici pertinenti, sulla base di principi equivalenti alle disposizioni della direttiva 2001/20/CE. Le sperimentazioni devono essere eseguite conformemente ai principi etici contenuti ad esempio nella dichiarazione di Helsinki. 2
PROBLEMATICHE ETICHE NELLE SPERIMENTAZIONI NEI PAESI IN VIA DI SVILUPPO (PVS) Sempre più sperimentazioni vengono condotte nei paesi in via di sviluppo. Si stima che il 20-30% dell attività di sperimentazione clinica globale sia svolta in tali Paesi. Le sperimentazioni riguardano spesso patologie dei Paesi sviluppati (es.colesterolo, depressione, ecc) e patologie come malaria e tubercolosi presenti nei PVS. Motivazioni: 1) Bassi costi 2) sperimentazioni più brevi 3) standard etici meno vincolanti e minori controlli AIM of The Trial audited: to detect the efficacy and safety of an IMP versus Placebo in the early treatment of patients who cannot obtain standard care immediately COUNTRIES in Africa and ASIA 6 3
MAIN STEPS OF THE TRIAL Some of the inclusion criteria: patients with: a) clinical symptoms/diagnosis of pathology under study b) patients who do not have and cannot obtain standard care immediately 7 1. Involvement of the population of Villages to explain the Clinical Trial ( Community mobilization ), to obtain the Community Consent; 2. Selection and training of Field Workers in villages (F.W.); 3. Investigators visit villages and communities within the area that provide their permission to identify and train F.W.s 4. Medication randomised to IMP or Placebo and provided to FWs 8 4
5. FWs trained to identify patients with clinical symptoms and to treat if: a) the patient meets the inclusion/exclusion criteria b) the standard of care is not available c) I.C. has been given in writing; d) patients or guardians say that they agree to go to nearest health facility; e) a biological sample to confirm diagnosis is willingly provided 6. The patient is treated and referred to health facility where patient can receive: a) definite diagnosis b) standard treatment Some of the Main Issues audited: I) Ethical Aspects related to Placebo II) Ethical and operational aspects related to Informed Consent (IC) III) Field Workers (F.W.) selection, training and SOPs IV) SOPs and operational measures related to treatment 10 5
I) ETHICAL ASPECTS RELATED TO PLACEBO 1) Proof that C.T. received a favorable opinion : a) by an international or E.U. Ethics Committee (ETH.C) in compliance with GCP b) by independent local Ethics Committees in compliance with GCP requirements 2) Proof that members of ETH.Cs had no conflict of interests 3) Documentation showing that the placebo issue has been suitably discussed by the ETH.Cs and in the protocol 11 4) Documentation showing that the discussion on placebo took into consideration: a) the GCP principle 2.3; the Declaration of Helsinki point 2.1. ; The rights, safety and wellbeing of the trial subjects should prevail over the interest of science and society. b) whether in the local environment there was or was not available an effective treatment/standard of care that could be used instead of placebo; c) whether another design was possible eg was it possible or not possible to compare IMP treatment versus historical data available in the scientific literature. 12 6
5) Documentation showing that all concerns of ETH.Cs had been solved and that before the beginning of C.T. sponsor/investigators answered satisfactorily all questions raised by ECs 6) Documentation showing ETH.Cs periodic review of C.T., mainly to possible problems related to placebo 13 II) ETHICAL AND OPERATIONAL ASPECTS RELATED TO INFORMED CONSENT 1. Documentation and interviews with investigators and FWs showing that I.C. were obtained, respecting local traditional customs: i.e. involvement and information provided to: a) chiefs of villages and traditional healers of villages; b) other villages leaders and religious leaders; c) the whole community or village (Community Consent Seminars); d) patients or patients' guardians; 14 7
III) Field Workers (F.W.) requirements, training, selection and SOPs 2. Documentation of how people understood the principle of the placebo? 3. Why they accepted the possibility of placebo? 4. Whether it was possible to check the finger prints on informed consent document? 15 1) Documentation showing and/or interview confirming: a) Presence of minimum requirements foreseen for F.W. and for F.W. Supervisors (F.W.S.) b) Contents and methodology and material of training courses: list of trainers and trainees c) F.W. and F.W.S. content of learning/selection 16 8
d) Provision of material for F.W. as: Training course brochure SOPs F.W. Diary/note books CRF F.W.S. Registers for traceability of main steps of C.T. Material for finger prints for IC Material for taking biological samples Thermometer etc. IMP in packaging that would prevent contamination in remote villages Bicycle, etc 17 IV) SOPs and operational measures related to treatment and related source documents : e.g. 1) Clear SOPs/written instructions for treatment: a) I.C., patients recruitment; treatment; traceability of treatment; etc b) use of treatment code labels and identifiers (stickers) for each treatment that were stuck on: CRFs; biological samples tube; I.C. forms 18 9
c) for consequent problems related to: - cases of more than one treatment for the same patient (e.g. 2 stickers on CRF) 2) SOPs for management of FW s notebook/diaries - cases of more than one sticker on biological sample tube taken 3) Source Documents: A) F.W. Diaries/notebooks - consistent items in the CRF - consistent training for FW 19 20 10
B) F.W.Registers with information about traceability of CT crucial steps, i.e. a) date and time of symptoms; b) date and time of other treatments before randomization; c) date and time of treatment; d) if the IMP was damaged and its code N ; e) in case of d): if another IMP was used and its code N ; f) date and time of: biological sample taken biological sample given to laboratory whether patient referred to health facilities - whether patient arrived at facility standard of care given in the health facilities diagnosis in health facilities results of biological sample analysis etc 21 11
4) Registers: - List of FW Supervisors and of their FWs - Register with periods of work of FW and FWS - List of villages/community within the responsibility of each FW 5) Interviews confirming: F.W. approach to obtain I.C. F.W. methodology for IMP treatment F.W. methodology to convince patients (or guardian) to proceed to health facilities for standard of care diagnosis and management etc. etc 23 24 12
GRAZIE PER L ATTENZIONE 13