Ingrid Callies Legal Counsel October 5, 2006

1. The French National Agency for Research on Aids and Viral Hepatitis – Clinical Research Legislation: A French Experience Ingrid Callies Legal Counsel October 5, 2006

2. Introduction: The ANRS and Research on HIV Vaccines • The ANRS finances research projects and sponsors clinical trials. • For over ten years the ANRS has been committed to an original research program on HIV vaccines, combining basic science and clinical research. Between 10 and 20% of its budget is dedicated to the preventive vaccine research effort. • In addition, the ANRS is sponsoring clinical trials taking place in a therapeutic vaccine approach, on HIV seropositive patients.

3. Introduction: Clinical Research Legislation in France (1) • The legislation governing clinical research in France is found in the French Code of Public Health (Code de la Santé Publique). It has been updated recently, both in 2004 and 2006. • One of the main objects of the 2004 Law was the transposition into French law of the European directive 2001/20/CE obligating member States to harmonize their legal, regulatory, and administrative provisions for the conduct of clinical trials on medicinal products for human use.

4. Introduction: Clinical Research Legislation in France (2) • Whereas the European Directive applies only to "clinical trials on medicinal products“ - it is not concerned with physiopathological and cognitive research - French law covers biomedical research in a broader sense. In particular, it covers research in "the behavioral sciences". • However, following the modifications made to French law in 2004, non-interventional trials are not ruled by the part of the French Health Code applicable to biomedical research.

5. Clinical Research in France: the Necessary Approvals • In order to conduct a clinical research project in France, the sponsor needs to have both: 1)the approval of an ethics’ committee now called Committee for the Protection of Persons, set-up by the state in the Regions of France and, 2)the authorization of the competent authority, ie AFSSAPS for trials on medicinal products. • In addition, the sponsor needs to fulfill the obligations set forth by the law on data process and liberties, as applied by a French agency, ie CNIL.

6. The Network of Volunteers • The setting-up of vaccine trials is contingent upon recruitment of suitable volunteers in whom the candidate vaccines are evaluated. • 1992: setting-up of a multidisciplinary committee to select candidates composed of ANRS representatives, clinicians and psychiatrists/psychologists. • Volunteers: 1) must be seronegative, 2) not exposed to risks of contamination, and 3) must understand and accept the risks associated with the research.

7. The Main Risks Taken into Account by the Volunteer Selection Procedure • A biological risk: the vaccine preparations tested may induce the production of antibodies which, in case of contact with HIV, facilitate contamination. • A behavioral risk: a volunteer who believes him/herself to be unduly protected by a candidate vaccine could adopt behaviors that heighten the risk of HIV contamination. • A psychological pressure: Participants in vaccine trials may produce anti-HIV antibodies. They are in a situation of « pseudo-seropositivity » or « seropositivity without the virus ». A screening test may be positive even though they are not carrying the virus. • A social pressure: The situation of pseudo-seropositivity may prove problematical in certain situations (crossing the borders of certain countries, obtaining insurance when applying for a loan…).

8. The Call for Volunteers and the Selection Process (1) • The call is made through radio, television and written press. A free phone number is given to the public. The persons answering the phone calls are trained to answer the main questions. • The persons interested may call the free phone number and request a file that contains a number of documents: • A letter from the director of the ANRS • A general information document: « Volunteers for a Vaccine » • A questionnaire as to the identity of the person and his or her motivations • A document specific to women who may become pregnant

9. The Call for Volunteers and the Selection Process (2) • If the person is still interested he or she fulfills the questionnaire and sends it back to the ANRS. In certain cases a medical doctor will call the person for further questions. • A first selection is made by a committee. Following this selection a written response is sent by the ANRS to the volunteers. For the persons preselected the letter offers an appointment with one of the clinical investigation sites. • At the appointment the person: meets a medical doctor and a psychiatrist or a psychologist. • The medical doctor hands the person: • A form giving information and requiring consent to participate in the selection. • The consent must be signed before the consultation and the biological exams which include an HIV serology. • The doctor and psychiatrist/psychologist are given by the ANRS a guide for the consultation.

10. The Call for Volunteers and the Selection Process (3) • The final selection is then made by the selection committee. The result of the selection is given orally to each person by one of the investigators. • The selected persons receive a letter from the director of the ANRS together with a consent form to become part of the network. This consent is not a consent to participate in a clinical trial. This consent only means that the person may be contacted by the ANRS for a future clinical trial. • The ANRS created in 1992 a data file containing the name and address of each volunteer. This data file has been approved by the French agency for the protection of data and liberties (CNIL). The creation of the network has been approved by a Committee for the Protection of Persons in research (Comité de Protection des Personnes).

11. For Each New Trial :The Enrolment of Subjects in an ANRS Clinical Trial • At the ANRS, the protocols for any new clinical trial are discussed in depth by specialists’ committees. In each of these committees NGO representatives are present. The ANRS has a long standing collaboration with NGOs representing HIV-positive patients. • In addition to this review, the protocol, the information document and the consent form are reviewed and amended by NGO representatives. The purpose of this review is for the information to be understood by the patients and volunteers enrolled in one of our trials. • The volunteers contacted by the ANRS, as well as patients meeting the inclusion criteria are informed by the investigator of the objectives, risks and benefits of the trial and ask to sign a consent form.

12. An ANRS Experience: the Suspension of the ANRS Vac 18 Trial • Following a myelitis event in a trial using lipopeptides in the USA, the ANRS Vac 18 Trial was temporarily suspended on request from the French Health Product Safety Agency (Afssaps). • The trial was authorized to go forward. • However, in accordance with the experts’ opinions, new exclusion criteria and further follow-up for the occurrence of neurological and ophthalmologic symptoms were added. During this whole process, the volunteers were kept informed by the ANRS of the evolution of these issues.

13. Research in the Developing World Research in the developing countries is one of the priorities of the ANRS, which intends to incorporate in its vaccine program those countries in which there are ANRS sites. This program involves three principal lines of attack: • Analysis of the viral sequences present in the Ivory Coast population. • Evaluation of the immune response to determine whether the utilization of lipopeptides designed from sequences of the subtype B virus is relevant in populations infected by other viral subtypes. • Setting up the infrastructure needed for recruitment of volunteers and for a future clinical trial (phase III trial). This last issue raises numerous ethical issues that we are trying to address.