Transcript Declaration of Helsinki

II French-Chinese
Bioethics Workshop
Paris 22, 23 February 2007
Jiali LI, MD, Ph.D
Cancéropôle Île de France
(Cancer Agency of Paris Area)
Declaration of Helsinki
A statement of ethical principles developed by the World
Medical Association to: "provide guidance to physicians and
other participants in medical research involving human
subjects" (Para 1, Declaration of Helsinki).
The Declaration was first adopted in 1964 and has since
undergone several revisions (1975, 1983, 1989, 1996, and in
2000) to accommodate advances in medical science and
ethical problems.
Declaration of Helsinki
The basic idea of the Declaration is to bind the physician with
the words, the health of my patient will be my first
consideration," and the International Code of Medical Ethics
declares that, "A physician shall act only in the patient's
interest when providing medical care which might have the
effect of weakening the physical and mental condition of the
patient."
The Declaration is considered a fundamental document in
the ethics of healthcare research. As a result, the principles
have been embodied in subsequent international guidance
and regulations.
The 13 principles of GCP
 Clinical trials should be conducted in accordance with the
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ethical principles that have their origin in the Declaration of
Helsinki, and that are consistent with GCP and the applicable
regulatory requirement(s).
Before a trial is initiated, foreseeable risks and inconveniences
should be weighed against the anticipated benefit for the
individual trial subject and society. A trial should be initiated and
continued only if the anticipated benefits justify the risks.
The rights, safety, and well-being of the trial subjects are the
most important considerations and should prevail over interests
of science and society.
The available nonclinical and clinical information on an
investigational product should be adequate to support the
proposed clinical trial.
Clinical trials should be scientifically sound, and described in a
clear, detailed protocol.
The 13 principles of GCP
 A trial should be conducted in compliance with the
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protocol that has received prior institutional review
board (IRB)/independent ethics committee (IEC)
approval/favourable opinion.
The medical care given to, and medical decisions
made on behalf of, subjects should always be the
responsibility of a qualified physician or, when
appropriate, of a qualified dentist.
Each individual involved in conducting a trial should
be qualified by education, training, and experience to
perform his or her respective task(s).
Freely given informed consent should be obtained
from every subject prior to clinical trial participation.
The 13 principles of GCP
 All clinical trial information should be recorded,
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handled, and stored in a way that allows its accurate
reporting, interpretation and verification.
The confidentiality of records that could identify
subjects should be protected, respecting the privacy
and confidentiality rules in accordance with the
applicable regulatory requirement(s).
Investigational products should be manufactured,
handled, and stored in accordance with applicable
good manufacturing practice (GMP). They should be
used in accordance with the approved protocol.
Systems with procedures that assure the quality of
every aspect of the trial should be implemented.
International guidance and regulations on
Biomedical researches
 Declaration of Helsinki (1964)
 Loi Huriet (1988, in France)
 ICH-GCP (1997)
 Clinical Trials European Directive (2001/20/EC)
 Good Clinical Practice European Directive
(2005/28/EC)
Major specificity of Phase I study in
Oncology
 Not allowed in Healthy volunteers
 be undertaken only in cancer patients without
established therapeutic alternatives with
advanced or metastatic disease.
( fundamental reason causing
the
specificity)
Responsibilities of Investigator-Compliance
with Protocol
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The investigator/institution should conduct the
trial in compliance with the protocol agreed to
by the sponsor
The investigator should not implement any
deviation from, or changes of the protocol
without agreement by the sponsor and prior
review and documented approval/ favorable
opinion from the IRB/IEC of an amendment,
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Possible violation of inclusion criteria
in a phase I study
 Age between 18 and 75 years
 Adequate hematological counts (neutrophils  1.5 x
109/l, platelets  100 x 109/l, hemoglobin  9 g/dl)
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In reality,
Age’s problem
Neutrophiles ‘s problem: no upper-limit
Another specificity-Death during study
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Phase I study should normally be undertaken in
cancer patients without established therapeutic
alternatives with advanced or metastatic disease.
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Disease could be progressed easily by multiple
causes (cachexia)
death (not necessary
related to study product)
Serious Adverse Event (SAE)
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Any untoward medical occurrence that at any
dose :
 results in death,
 is life-threatening,
 requires inpatient hospitalization or prolongation of
existing hospitalization,
 results in persistent or significant
disability/incapacity,
or
 is a congenital anomaly/birth defect
Notification of serious adverse events
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The investigator shall report all serious adverse
events
immediately to the sponsor except for those that the
protocol
or investigator's brochure identifies as not requiring
immediate
reporting. The immediate report shall be followed by
detailed,
written reports.
 Generally, SAE, whether or not considered as related to
study drug, must be reported on a SAE form and faxed to
the Sponsor within 24 hours of occurrence or Investigator’s
knowledge of this event.
Negligence of reporting the death caused by
disease progression
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Investigator judges himself that the death is cased by
disease progression
not report it
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No respect /ignorance to GCP (Reporting/ additional
requested information)
Assuring the quality of clinical data
in Paris Area
 Writing SOPs cover all aspects of a clinical trial, including:
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protocol preparation
ethical approval
assessing and monitoring trial sites
safety data reporting
checking data integrity
clinical report writing
etc.
Implementing SOPs in every sites of Paris Area (by the end of
June 2007)
Training of investigators
France has launched its national
plan to fight cancer on 23th March 2003
7 Cancéropôle cancer centers have been set up to bring
together the major research bodies
The Paris Region Cancéropôle Cancer Centre
(Cancéropôle île de France)
presided by Prof. Claude Huriet
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Being the head of the French Cancéropôle network
Its mission is o federate skills and research
capabilities in cancer research in the Paris Region
through 7 Areas
Seven areas inside of Cancéropôle Ile
de France
 Tumor identify cards
 From tumor biology to innovative cancer treatments
 Host-tumor relationship: immune responses, angiogenesis
 Targeted screening and specific prevention of cancer
 Functional imaging of cancer
 New clinical research with novel tolls for the definition and
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evaluation of clinical trials
Human and social science
Area 6: Clinical Research
Its principal goal is to ensure the new and effective
treatments will be available more readily to patients
The bureau of Phase I/II oncology
study inside of Area 6
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Represented by
Jiali LI, Chief Manager, MD, PhD
Karine Buffard, Assistant Manager, Pharm.D
Hôpital Saint-Louis
1 Ave. Claude Vellefaux
75010 Paris, FRANCE
Tel. 33-1-4803-7244
[email protected]
karine. [email protected]
Executive committee constituted by
Top French Authorities
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Pierre BEY (Institut Curie)
Véronique DIERAS (Institut Curie)
Fabien CALVO (AP-HP)
Michel MARTY (AP-HP)
Olivier RIXE (AP-HP)
Jean Nicolas MUNCK (Centre René Huguenin)
Eric Angevin (Institut Gustave Roussy)
Gilles VASSAL (Institut Gustave Roussy)
Active and confidential services to biotechnology
companies
 Advisory assistance in project planning
 Methodological advice in preparation of protocols and case
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report forms, etc.
Help choosing suitable investigation centers
Assistance with administrative procedures
Guarantees of timetabled inclusion of patients
Assurance of study quality
Direct contact with any member of our Executive Committee,
most of who are leading authorities in
France, as well as in the European Union
France, world leader in development
of new anti-cancer agents
Evidence for the efficacy of many anti cancer
drugs was first provided in France.
CPT-11
 CPT-11 was synthesized by Yakulto Honsha (Japan)
 Marketing approval in January 1994 in Japan, for the treatments
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of non-small cell and small cell lung cancers, cervical cancers,
and ovarian cancers.
Marketing approval in France in May, 1995, for the treatment of
advanced colon cancers. (Rhone-Poulenc Rorer )
Licensed in Japan in September 1995 for the treatment of
patients with colorectal cancer
Marketing approval in the USA in June 1996 for the treatment of
patients with colorectal cancer
Oxaliplatin
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Invented in 1976 by Dr. Kidani (Japan)
Marketing approval with the indication of colorectal
cancer in France in 1996
Marketing approval in the USA in 2002 with same
indication
Marketing approval with the same indication in Japan
in March, 2005
Taxotere
 Discovered by Pierre Potier (CNRS, France)
 1994 received the first marketing authorizations from Mexico
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and South Africa for the treatment of advanced breast cancer in
patients
1995: the first oncology drug to complete the European Union's
new centralized review procedure and receive regulatory
clearance in all 15 member countries in the treatments of
patients with advanced stage breast cancer
1996 Market approval for the US
Navelbine (Vinorelbine)
 Discovered by Pierre Potier (CNRS, France ) in 1978
 First Marketing approval in France in 1989 in NSCLC by Pierre
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Fabre
the American FDA in 1994 in NSCLC
France, world leader in development
of new anti-cancer agents
Eight anti-cancer drugs are manufactured in France for the rest
of the world.
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The Eli Lilly laboratories’ site for the worldwide supply of Alimta is
in Alsace
Ipsen produces Decapeptyl and Somatuline in France for the rest
of the world
Exolatine is packaged in France for about fifty countries.
Aventis Pharma has a production factory Taxotere for the rest of
the world
The same is true for Fasturtec, Gemzar and Vinorelbine.
France, the most active region in
cancer clinical research
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For exemple
In 2002, 6241 patients participated into clinical studies organized
by EORTC (European Organization for Research and Treatment of
Cancer, the biggest European cancer research network.
The highest number of patients included into studies were:
 France 1262
 The Netherlands: 1261
 The United Kingdom: 716
 Germany: 426
France, one of the countries with the
highest speed to market for drugs
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France is the only country in Europe having a procedure for premarket approval (ATU)
ATU procedure is an exceptional measure for marketing drugs
available that do not have marketing approval.
The aim is to enable early access to new treatments when they are
to be used for treating patients with serious disease and when
there is no therapeutically alternative.
ATU is issued by the AFSSAPS( the French National Drug Agency)
Facilities for clinical cancer research
in Paris Area
 2 main French and European reference cancer centers :
Gustave Roussy Institute, Curie Institute
 A third French cancer center, the René Huguenin center
 The biggest hospital network in Europe: the AP-HP (Assistance
Publique-Hôpitaux de Paris) including 14 establishments in
Oncology
The Gustave Roussy Institute
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Established in 1921, the leading European anticancer centre
2,500 employees
Fifteen departments with 400 beds
30,000 patients attend its clinics and 42,000 patients treated and
11,000 new patients per year
More than 400 researchers working in 11 research units
Technology platform: tumor biology, host-tumor interaction,
functional/metabolic imaging, epidemiology, healthcare economics
Almost 20 years experience in conducting Phase I/II studies
12 Phase I trials, 14 Phase I/II trials and 47 phase II have been
conducted in the Institute during the year of 2004
Curie Institute
 Established in 1921 by Marie Curie and Claudius
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Regaud
>1,700 people employees
>650 researchers working in 12 research units
227-bed with 27 departments
8,000 new patients are treated each year
Technology platform: Genomics, bioinformatics,
pharmacology, immunology; functional imaging
More than 100 clinical trials including studies
sponsored by the Institute are conducted each year
during the last 4 years
Centre René Huguenin
 Founded in 1959
 2500 new cases of cancer each year including
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>1000 breast cancer
Established in 1959
650 employees
150 beds
Technology Platform: tumor bank/serum bank;
genomics, pharmacokinetics; host-tumor
relationships; Oncogenetics, metabolic/functional
imaging
Long experience for conducting phase I/II studies
of new anti cancer agents
Assistance Publique-Hôpitaux de Paris
(AP-HP)
 Biggest hospital network in Europe
 39 establishments with >25,000 beds
 With 32% of hospital admissions in oncology in the
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Paris Region (40 800 new patients a year)
16 of them have particularly well-developed oncology
6 sites are highly specialized in oncology practice and
clinical study