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
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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.”
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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.
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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
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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
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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
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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
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I) ETHICAL ASPECTS RELATED TO
PLACEBO
1)
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”.
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
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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.
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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
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:
6) Documentation showing ETH.Cs periodic review of C.T.,
mainly to possible problems related to placebo
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;
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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?
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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
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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
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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
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c) for consequent problems related to:
- cases of more than one treatment for the same patient
2) SOPs for management
notebook/Diaries
of
FW’s
(e.g. 2 stickers on CRF)
- 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
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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
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4) Registers:
5) Interviews confirming:
- List of FW Supervisors and of their FWs
F.W. approach to obtain I.C.
F.W. methodology for IMP treatment
- Register with periods of work of FW and
FWS
- List of villages/Community within the
responsibility of each FW
F.W. methodology to convince patients (or
guardian) to proceed to health facilities for
standard of care diagnosis and management
etc.
etc
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GRAZIE PER L’ATTENZIONE
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