1. II French-Chinese Bioethics Workshop Paris 22, 23 February 2007 Jiali LI, MD, Ph.D Cancéropôle Île de France (Cancer Agency of Paris Area)

2. 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.

3. 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.

4. The 13 principles of GCP  Clinical trials should be conducted in accordance with the 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.

5. The 13 principles of GCP  A trial should be conducted in compliance with the 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.

6. The 13 principles of GCP  All clinical trial information should be recorded, 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.

7. 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)

8. 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)

9. Responsibilities of Investigator-Compliance with Protocol  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, ….

10. 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) In reality,  Age’s problem  Neutrophiles ‘s problem: no upper-limit

11. Another specificity-Death during study  Phase I study should normally be undertaken in cancer patients without established therapeutic alternatives with advanced or metastatic disease.  Disease could be progressed easily by multiple causes (cachexia) death (not necessary related to study product)

12. Serious Adverse Event (SAE)  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

13. Notification of serious adverse events  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.

14.  Investigator judges himself that the death is cased by disease progression not report it  No respect /ignorance to GCP (Reporting/ additional requested information) Negligence of reporting the death caused by disease progression

15. Assuring the quality of clinical data in Paris Area  Writing SOPs cover all aspects of a clinical trial, including: 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

16. 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

17. The Paris Region Cancéropôle Cancer Centre (Cancéropôle île de France) presided by Prof. Claude Huriet  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

18. 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 evaluation of clinical trials  Human and social science

19. Area 6: Clinical Research Its principal goal is to ensure the new and effective treatments will be available more readily to patients

20. The bureau of Phase I/II oncology study inside of Area 6 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 jiali.li-vibert@canceropole-idf.com karine. buffard@canceropole-idf.com

21. Executive committee constituted by Top French Authorities  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)

22. Active and confidential services to biotechnology companies  Advisory assistance in project planning  Methodological advice in preparation of protocols and case 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

23. France, world leader in development of new anti-cancer agents Evidence for the efficacy of many anti cancer drugs was first provided in France.

24. CPT-11  CPT-11 was synthesized by Yakulto Honsha (Japan)  Marketing approval in January 1994 in Japan, for the treatments 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

25. Oxaliplatin  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

26. Taxotere  Discovered by Pierre Potier (CNRS, France)  1994 received the first marketing authorizations from Mexico 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

27. Navelbine (Vinorelbine)  Discovered by Pierre Potier (CNRS, France ) in 1978  First Marketing approval in France in 1989 in NSCLC by Pierre Fabre  the American FDA in 1994 in NSCLC

28. France, world leader in development of new anti-cancer agents Eight anti-cancer drugs are manufactured in France for the rest of the world.  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.

29. France, the most active region in cancer clinical research  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

30. France, one of the countries with the highest speed to market for drugs  France is the only country in Europe having a procedure for pre- market 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)

31. 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

32. The Gustave Roussy Institute  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

33. Curie Institute  Established in 1921 by Marie Curie and Claudius 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

34. Centre René Huguenin  Founded in 1959  2500 new cases of cancer each year including >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

35. 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 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