Ressource pédagogique : Cardiovascular Clinical Trialists (CVCT) Forum – Paris 2012 : Omics research and system biology. Keys for future personalized medicine How future trials may help optimizing benefit-to-risk ratio. The role of specialist scientific organizations.

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Title : Cardiovascular Clinical Trialists (CVCT) Forum – Paris 2012 : Omics research and system biology. Keys for future personalized medicine How future trials may help optimizing benefit-to-risk ratio. The role of specialist scientific organizations. ISCP: Speaker: Felipe MARTINEZ, Cordoba, ARG CVCT: Speaker: Faiez ZANNAD, Nancy, FRA ESC Working group in Pharmacology and Drug Therapy : Speaker: Christian TORP-PEDERSEN, Copenhagen, DEN Abstract : Cardiovascular medicine and drug development: time for a new trial paradigm Over several decades the event rates in trials have come down and this is frequently attributed to improved treatment of patients. Nevertheless, epidemiological studies of populations have failed to confirm the dramatic decline of event rates in the diseases studies. Over the same decades the conduct of clinical trials have become increasingly industrialized and the introduction of multiple interests that conflict with the scientific conduct of trials have been introduced. To understand the changes and devise a remedy it is important to examine the two key components of a trial – the patient and the investigator. A patient generally enters a trial for his own interest rather than a dedication to science. A trial must therefore be designed to increase the interest of patients and keep the burden at a minimum. The study must be explained briefly and accurately in the patient information. Multiple pages of information decrease the interest and also decrease the understanding. The number of physical visits must be kept at a minimum, in particular multiple screening visits during the initiation of a study is a burden. While double blind treatment is important, it should be avoided when the actual treatment is revealed for many patients which is the case when the effect or side effect of treatment are obvious. The investigator should be put in a situation where the motivation is to include representative patients without bias. This involves the protocol, the monitoring and the contract. A key motivation is a feeling of ownership. Trials are better when run by a moderate group of dedicated investigators rather than hundreds spread over the planet. The paperwork of trials must be kept at a minimum rather than the current maximum where even the work load of signing papers is significant. The contract is most likely the key to better conduct. The current contract design place all uncertainty on the investigator and trials can be postponed or stopped with no warning and no compensation. If a patients discontinues in a trial payment stops motivating investigators only to include patients that are unlikely to stop. Sick patients requiring multiple visits increase the cost for investigators without compensation. The remedy for trial design can only come about from a combined understanding and effort of industry and authorities. Both parties need to understand not only the principles of double blind but the effect is has on patients. Inclusion of representative patients is as important as other main principles of trial design. Authorities and industry need to accept that international patient representation may hamper good trial conduct. And the contracts need to change so that investigators are encouraged to include representative patients rather than patients that protect the economy of a trial. L’auteur n’a pas transmis de conflit d’intérêt concernant les données diffusées dans cette vidéo ou publiées dans la référence citée. 9th Global Cardiovascular Clinical Trialists Forum • Paris 2012 ESC Working group on cardiovascular pharmacology and drug therapy International Society of Cardiovascular Pharmacotherapy (ISCP) CardioVascular Clinical Trialists (CVCT) Joint session PERSONALIZED CARDIOVASCULAR MEDICINE AND DRUG DEVELOPMENT: TIME FOR A NEW TRIAL PARADIGM Chairpersons: Juan Carlos KASKI, London, GBR - Bertram PITT, Ann Arbor, USA - Luis RUILOPE, Madrid, ESP - “Drugs, in general, act not on single targets operating in a vacuum, but perturb a complex network of interacting proteins or metabolites to modify the dynamic output of a system that can extend well beyond the pathway in which the original target is operative. Therefore, to develop drugs in this century, one needs to move beyond the  reductionist biomedical science of Occam, Descartes, Osler, and Ehrlich, and consider the complex biological system within which a drug acts holistically, in its tractable entirety. One needs to apply the principles of systems biology to pharmacology, and thereby establish the new discipline of systems pharmacology.” Dr Joseph Loscalzo, Lewis A. Conner Lecture, Circulation 2012. - “We need to develop a robust, viable business model through which the pharmaceutical industry can move from drug development strategies that are population-based to strategies that focus on increasingly individualized therapies. There needs to be an alignment of incentives that move the industry from conventional blockbuster drugs developed in large populations with single drug targets within which one size fits all toward smaller, better defined systems pharmacologybased molecular pathophenotypes that benefit from these well conceived therapies with minimal risk.” Dr Joseph Loscalzo, Lewis A. Conner Lecture, Circulation 2012. - “Heart Failure is not a disease and we should no longer approve drugs for a heterogeneous broad population, but for a well defined sub-population where we can demonstrate a marked benefit” Dr. Stephen Grant, Deputy Director, Division of Cardiovascular Renal Products, CDER - “Regulatory bodies like the FDA and the EMA will most likely require new trials to scrutinize events (i.e. AMI) very strictly. Well conducted registries will be important in this context so clinicians can report their findings in real life patients. Academic institutions and independent pharmacological and pharmacotherapy associations such as ISCP should provide mechanistic data as to the possible reasons for the detected increased prevalence of MI in some patient groups receiving treatment with direct thrombin inhibitors. Lessons learned with other new pharmacological agents in the past will necessarily require that the medical and pharmacological communities together with industry and regulatory agencies take up the challenge and work synergistically and in synchrony to clarify the side effects and excess MI risk – albeit minimal according to current studies - associated with the newer anticoagulants. - We are all now at the start of a long and winding road that should hopefully take us to better understand the mechanism of action, the therapeutic efficacy and the adverse effects associated with the use of the new anticoagulants. Together we should prevent unnecessary complications that might derive from the use of these important agents in the wrong patient groups.” Juan Carlos Kaski, Cardiovasc Drugs Ther, 2012 Réalisation, production : Canal U/3S et CERIMES Keyword : Cardiovascular Clinical Trialists, Paris, 2012, Cardiovascular prevention, cardiovascular pharmacology, ISCP

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