Teaching Slides Collection

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH Promoting the responsible conduct of biomedical research 10th-‐14th November 2014 University of Insubria Varese -‐ Italy

Teaching Slides Collection Module #3 of 5 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS Under the Auspices of

http://www.istruzione.it/

Organizing Secretariat Center of Research in Medical Pharmacology, University of Insubria Via Ottorino Rossi n. 9, 21100 Varese VA, Italy Phone: +39 0332 217401-‐397401 -‐ Fax: +39 0332 217409-‐397409 E-‐mail [email protected]

Center of Research in Medical Pharmacology, University of Insubria Via Ottorino Rossi n. 9, 21100 Varese VA, Italy Phone: +39 0332 217401-‐397401 -‐ Fax: +39 0332 217409-‐397409 E-‐mail [email protected]

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH Promoting the responsible conduct of biomedical research 10th-‐14th November 2014 University of Insubria Varese -‐ Italy

Teaching Slides Collection Module #3 of 5 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS

Index

A chi è indirizzata questa School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS -‐ Biosketches page 5 Module #3 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS page 9 OTHER MODULES Module #1 RESEARCH INTEGRITY Module #2 PRECLINICAL RESEARCH AND LABORATORY ANIMAL CARE AND USE Module #4 PUBLISH OR PERISH Module #5 UNDERSTANDING BIOMEDICAL RESEARCH PAPERS

A chi è indirizzata questa School?

Esistono molteplici motivazioni di carattere sia generale che contingente che inducono a ritenere che ogni università e istituzione scientiRica debba quanto prima farsi carico della responsabilità di prevenire la cattiva condotta scientiRica, adottando tutte le misure necessarie a rendersi garante della qualità e della riproducibilità dei risultati dell'attività di ricerca scientiRica dei propri ricercatori.

Le iniziative più efRicaci per la prevenzione della scienti'ic misconduct devono prima di tutto prendere in considerazione la formazione dei giovani ricercatori. Studenti di dottorato e ricercatori post-‐dottorato dovrebbero ricevere un adeguato addestramento sulle metodologie e l'etica della ricerca scientiRica, in modo da comprendere che evitare pratiche discutibili è la scelta migliore non solo per garantire la qualità dei risultati, bensì anche per promuovere in maniera efRicace e corretta la propria carriera scientiRica.

Questo addestramento deve avvenire nel contesto di strategie appropriate implementate attraverso una esplicita politica dell'istituzione. Ad oggi le università sono prevalentemente preoccupate di attrezzarsi a reagire alle accuse di cattiva condotta, mentre ognuna di esse dovrebbe prima di tutto prevenire la cattiva condotta dei propri ricercatori, anche considerando che la sua reputazione viene comunque danneggiata da eventuali casi che li possano coinvolgere. La prevenzione della scienti'ic misconduct e l'addestramento alla research integrity, indirizzato prima di tutto ai giovani ricercatori, deve diventare una priorità per le università, anche per tener fede ai loro obblighi e responsabilità istituzionali di natura etica e sociale.

Per approfondire Che cos'è l'integrità nella ricerca e perché è importante? Esiste una "emergenza etica" nella ricerca scientigica? Researcher bias, publication bias e scienti9ic misconduct

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Che cos'è l'integrità nella ricerca e perché è importante? L'adesione ai principi etici nella ricerca scientiRica promuove gli scopi più generali della ricerca stessa, quali accrescere la conoscenza, perseguire la verità e evitare l'errore. Inoltre, dal momento che in particolare nella biomedicina la ricerca richiede un grado elevato di cooperazione, le norme etiche promuovono valori essenziali al lavoro collaborativo, quali la Riducia, la responsabilità, il rispetto reciproco e la correttezza (si pensi alle linee guida per la authorship, il copyright, i brevetti, la condivisione di dati, la segretezza).

Molte norme etiche contribuiscono poi a garantire che i ricercatori sia in grado di assumersi la responsabilità delle proprie ricerche, dandone al tempo stesso pubblica garanzia, nei confronti della società, delle agenzie regolatorie e dei Rinanziatori. La percezione di un adeguato rigore etico nella ricerca scientiRica contribuisce poi a promuovere e consolidare il consenso pubblico nei confronti della ricerca scientiRica. I Rinanziatori, pubblici e privati, sono orientati a Rinanziare una ricerca nella quale possano riporre Riducia e che siano in grado di percepire come responsabile, di qualità e integra sotto ogni aspetto.

InRine, l'adozione di norme etiche per la ricerca scientiRica contribuisce a promuovere un insieme di importanti valori morali e sociali, quali la responsabilità sociale, i diritti umani, il benessere animale, il rispetto e l'aderenza alle leggi, la salute e la sicurezza.

Esiste una "emergenza etica" nella ricerca scientigica?

in uno studio pubblicato nel 2011 su Nature Reviews Drug Discovery alcuni ricercatori della Bayer dichiaravano di non esser stati in grado di replicare nei loro laboratori i risultati di circa due terzi di 67 studi preclinici pubblicati (la maggior parte dei quali in campo oncologico). Conseguenze di questa difRicoltà a replicare i risultati erano un considerevole allungarsi dei tempi della ricerca o anche, nella maggior parte dei casi, l’interruzione del programma di ricerca e sviluppo, dal momento che le evidenze ottenute non erano tali da giustiRicare ulteriori investimenti (e quelli già fatti, nel frattempo, erano sprecati).

In un altro studio, pubblicato nel 2012 su Nature, dei ricercatori della Amgen (una delle maggiori multinazionali di biotecnologie) riportavano di essere stati in grado di replicare i risultati di solo 6 su 53 studi pubblicati, nonostante si trattasse di studi selezionati in quanti considerati “pietre miliari” in campo ematologico e oncologico.

A simili conclusioni sono giunti anche i ricercatori dell’ALS Therapy Development Institute, la maggiore compagnia non-‐proRit nel campo della ricerca sulla sclerosi laterale amiotroRica, quando hanno tentato di replicare i risultati pubblicati a proposito dell’efRicacia di vari farmaci nel principale modello animale di questa devastante malattia: nessuno dei diversi farmaci testati ha confermato l’efRicacia descritta negli studi originali.

Il mancato rispetto dei principi di integrità nella ricerca scientiRica si riRlette concretamente in approssimazioni e spesso in veri e propri errori metodologici, organizzativi, tecnici e pratici tali da determinare un rischio inaccettabile di danno ai soggetti umani e animali coinvolti nella ricerca, ai ricercatori e più in generale all'istituzione e alla società nel suo complesso. D'altra parte, il mancato rispetto delle più elementari norme di sicurezza nei laboratori di ricerca può compromettere direttamente la salute di chi in essi lavora (o eventualmente li frequenta, ad esempio per motivi di studio).

Researcher bias, publication bias e scienti9ic misconduct

Negli ultimi anni si discute sempre più di fattori connessi al ricercatore (researcher bias) e al processo di pubblicazione (publication bias). I primi riguardano la pressione crescente subita dai ricercatori e che li forza a pubblicare sempre di più e sempre più rapidamente, per ragioni di carriera e/o per ottenere Rinanziamenti ulteriori. I secondi riguardano il desiderio delle maggiori riviste scientiRiche di pubblicare risultati nuovi e inaspettati, mentre le conferme di risultati già pubblicati o i risultati negativi di solito non vengono considerati interessanti.

La situazione italiana è a rischio estremamente elevato. Da un lato infatti l'Italia è tra i Paesi europei privi di linee guida e riferimenti su integrità scientiRica e promozione e repressione della scienti'ic misconduct. Dall'altro, la recente revisione della normativa sui concorsi universitari, con l'adozione di parametri bibliometrici quantitativi nella maggior parte dei settori disciplinari e in particolare nell'ambito biomedico, ha introdotto una inedita pressione a pubblicare "a qualsiasi costo", che già sta manifestando i suoi effetti, e le cui conseguenze saranno da studiare con attenzione.

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SPEAKERS & CHAIRS Walter Ageno -‐ University of Insubria Giuseppe Armocida -‐ University of Insubria Francesco Carù -‐ Biomedical Research Advisor, Milan Paolo Cattorini -‐ University of Insubria Marco Cosentino -‐ University of Insubria Francesco Dentali -‐ University of Insubria Alice Fabbri -‐ University of Bologna, Gruppo Nograzie Daniele Fanelli -‐ University of Montreal, CDN Marco Ferrari -‐ University of Insubria Malcolm Macleod -‐ University of Edinburgh, CAMARADES, SCO Franca Marino -‐ University of Insubria Tony Mayer -‐ Nanyang Technological University, Singapore Lorenzo Moja -‐ University of Milan Elena Monti -‐ University of Insubria Renzo Pegoraro -‐ PontiRicial Academy for Life, Rome Mario Picozzi -‐ University of Insubria Laura Ribeiro – University of Porto, P Anne Wilhelmina Saskia Rutjes -‐ University of Bern, CH Alessandro Squizzato -‐ University of Insubria Marco Taddia -‐ University of Bologna ORGANIZING COMMITTEE Marco Cosentino -‐ Franca Marino -‐ Mario Picozzi Walter Ageno -‐ Francesco Dentali Alessandro Squizzato SECRETARIAT Mrs. Paola Gervasini Center of Research in Medical Pharmacology University of Insubria Via Ottorino Rossi n. 9, 21100 Varese VA, Italy. Phone: 0332 217401-‐397401 -‐ Fax: 0332 217409-‐397409 E-‐mail [email protected] [email protected]

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SPEAKERS & CHAIRS Biosketches Walter Ageno -‐ University of Insubria

Walter Ageno is Associate Professor of Medicine at the University of Insubria and Director of the Short-‐Stay Medical Unit and Thrombosis Center at the Ospedale di Circolo of Varese, Italy. Dr. Ageno has authored and co-‐authored more than 300 articles indexed in MEDLINE, as well as several abstracts presented at national and international meetings and more than 10 book chapters in the 'ields of venous and arterial thrombosis. Dr. Ageno is chairman of the Scienti'ic Subcommittee of Control of Anticoagulation of the International Society on Thrombosis and Haemostasis, and chairman elect of the Scienti'ic Subcommittee board of the International Society on Thrombosis and Haemostasis. He is deputy editor for Thrombosis and Haemostasis, associate editor for the Journal of Thrombosis and Haemostasis and Internal and Emergency Medicine and member of the Advisory Board of Vascular Medicine. He has contributed to a number of national and international guidelines on venous and arterial thrombosis.

Giuseppe Armocida -‐ University of Insubria

Laureato in medicina e chirurgia, specialista in psichiatria e medicina legale e presidente della Società Italiana di Storia della Medicina. Ha insegnato nell’Università di Ancona, Bari e Pavia ed ora è professore ordinario di Storia della Medicina nell’Università dell’Insubria dove pure copre la didattica di Medicina delle comunità e Psicopatologia forense.

Francesco Carù -‐ Biomedical Research Advisor, Milan (I) Serving as designated veterinary surgeon he is involved in animal welfare protection, setting up of new models, preclinical procedures and technologies re'inement, high education and training in biomedical 'ield. Scienti'ic consultant on preclinical biomedical research for public Institutions (Academia, Hospitals) and member of Ethical Committees at public and private research Institutions. Main scienti'ic interests are, at time, the development of minimally invasive in-‐vivo techniques, the improvement of animal welfare in research and the development of alternative methods for education/training (mechanical and multimedia devices). He’s leading a team working on the 3R’s principles application in training and education (implementation of alternatives methods: multimedial devices and surgical simulators for dry-‐lab).

Paolo Cattorini -‐ University of Insubria

Professore ordinario di Medicina Legale, Università degli Studi dell'Insubria, Docente di Bioetica. Già componente del Comitato Nazionale per la Bioetica.

Marco Cosentino -‐ University of Insubria Professor of Medical Pharmacology, he holds a MD cum laude, University of Pavia, and a PhD in Pharmacology and Toxicology, University of Turin. Director of the Center for Research in Medical Pharmacology and of the School of Specialization in Medical Pharmacology. Coordinator of the PhD program in Experimental and Clinical Medicine and Medical Humanities. He served in several Ethics Committees for human and animal experimental research and contributed to writing the Academic Ethics Code of the University of Insubria.

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Francesco Dentali -‐ University of Insubria

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Alice Fabbri -‐ University of Bologna, Gruppo Nograzie Laureata in Medicina e Chirurgia nel 2008 e specializzata nel 2014 in Igiene e Medicina Preventiva presso l'Università di Bologna. Dal 2008 collabora con il Centro Studi e Ricerche in Salute Internazionale e Interculturale dell'Università di Bologna dove si occupa di attività di ricerca e didattica nei seguenti ambiti: etica e con'litto di interessi, salute globale, determinanti sociali e disuguaglianze in salute.

Daniele Fanelli -‐ University of Montreal Daniele Fanelli is Visiting Professor at the University of Montreal, Canada, af'iliated faculty at the Inter-‐University Centre for Research on Science and Technology, at the University of Quebec at Montreal, and is a member of the CNR Research Ethics and Bioethics Advisory Committee, Italy’s 'irst agency to deal with Research Integrity. Fanelli, who trained as an evolutionary biologist and a science journalist, is known for his empirical work on bias and misconduct in science, and in scienti'ic communication. He has authored several in'luential publications in the 'ield, including one of the most popular articles ever published in the Public Library of Science, which counts nearly 140,000 online views. His work and opinions are regularly cited in the popular press, and he has been involved at various levels with international conferences and initiatives, including the Council of Canadian Academies Expert Panel on Research Integrity and the organization of the 3rd World Conference on Research Integrity. [Further information can be found at danielefanelli.com]

Marco Ferrari -‐ University of Insubria

Graduated in Biological Sciences (University of Milano, Italy, 1995), quali'ication in Pharmacology (University of Pavia, Italy, 2001) and PhD in Pharmacology (University of Insubria, Italy 2009). From 2006 , Researcher in Pharmacology at the University of Insubria. Member of the PhD course in Clinical and Experimental Pharmacology, and of the PhD course in Experimental and Clinical Medicine and Medical Humanities. From 2004 member of Ethics Committees for human research.

Malcolm Macleod -‐ University of Edinburgh, CAMARADES

Centre for Clinical Brain Sciences, University of Edinburgh; and CAMARADES. Malcolm Macleod is Professor of Neurology and Translational Neurosciences at the University of Edinburgh, and is Clinical Lead for Neurology, Stroke and Acquired Brain Injury at NHS Forth Valley. His research interests include hypothermia as a treatment for acute ischaemic stroke; the potential bene'its of multicentre animal studies; and improving the quality of animal research. He is a member of the UK Home Of'ice Animals in Science Committee and of the UK Commission for Human Medicines.

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Franca Marino -‐ University of Insubria

Researcher in Medical Pharmacology, she graduated in Biological Sciences and took the PhD in Pharmacology at the University of Pavia. Coordinator of the PhD program in Clinical and Experimental Pharmacology, member of the Faculty of the PhD program in Experimental and Clinical Medicine and Medical Humanities. She served in several Ethics Committees for experimental research.

Tony Mayer -‐ Nanyang Technological University, Singapore Europe Representative and Research Integrity Of'icer, President’s Of'ice Nanyang Technological University (NTU), Singapore, Co-‐Chair of First and Second World Conferences on Research Integrity, Member, Euroscience Governing Board. Tony Mayer is a geologist educated at the University of Manchester following which he undertook research at the University of Leicester and later, at University College London. Tony Mayer joined the NTU, Singapore, as its Senior Science Of'icer and Associate Registrar, working closely with the Provost and including acting as its Research Integrity Of'icer.

Lorenzo Moja -‐ University of Milan Assistant Professor, University of Milan, Head, Clinical Epidemiology Unit, IRCCS Galeazzi Orthopaedic Institute. Lorenzo Moja is a clinical epidemiologist. Research interests: knowledge transfer, namely, the development and evaluation of interventions aimed to facilitate the movement of science into clinical practice and health policy in order to ensure optimal payback from health care and research investments. He has conducted numerous systematic reviews and meta-‐analyses, including Cochrane reviews, of medical interventions across diverse medical specialties, including neurology, oncology, orthopaedics, palliative medicine, and physiotherapy. He has also led knowledge transfer programs to evaluate point-‐of-‐care services (e.g. Clinical Evidence, UpToDate and Dynamed) for their editorial and evidence-‐based quality, and to disseminate evidence adopting new media technologies such as e-‐learning, point-‐of-‐care services, and computerized clinical decision support systems linked to electronic health records.

Elena Monti -‐ University of Insubria

Laureata in Scienze Biologiche (1980) e specializzata in Farmacologia (1994) presso l'Università di Milano. Dal 1998, professore di Farmacologia nell'Università dell'Insubria. Linee di ricerca, con modelli in vitro e in vivo, includono: cardiotossicità delle antracicline, resistenza ai chemioterapici antitumorali, effetti del microambiente ipossico suprogressione e metastatizzazione dei tumori. Autore di circa 90 articoli su riviste recensite e di capitoli su volumi. Ha presieduto il comitato Etico per la Sperimentazione Animale (CESA) dell'Università dell'Insubria dalla sua istituzione (1998) 'ino a maggio 2014.

Renzo Pegoraro -‐ PontiRicial Academy for Life Direttore Scienti'ico Fondazione Lanza, Padova (http://www.fondazionelanza.it/), Cancelliere Ponti'icia Accademia Pro Vita, Roma (http://www.academiavita.org/), Presidente del Comitato Etico dell'Istituto Oncologico veneto. Già Presidente dell'Associazione Europea dei Centri di Etica medica

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Mario Picozzi -‐ University of Insubria

Professor of Forensic Medicine and Clinical Bioethics, graduated in medicine at the University of Milan and specialized in Forensic Medicine at the University of Insubria. Appointed as expert by the National Center of Transplantations and by the Consiglio Superiore di Sanità (Health High Council), Coordinator of the Course on Bioethics, Catholic University of Sacred Hearth, Milan, member of the scienti'ic committee of the International Master in Medical Humanities, University of Insubria. He served in several Ethics Committees for human and animal experimentation and contributed to writing the Academic Ethics Code of the University of Insubria and is presently member of the Academic Ethics Committee.

Laura Ribeiro – University of Porto, Portugal

Professor at the Faculty of Medicine of the University of Porto since 1999. She holds a PhD in Human Biology (FMUP, 2007). Principal Investigator of the project “RES4MED: learning medicine through research” (EXPL/IVC-‐PEC/1302/2013) on the research area “Institutions, Values, Beliefs and Behavior – Education and Science Policy”, supported by Foundation for Science and Technology (https://www.fct.pt/apoios/projectos/consulta/vglobal_projecto? idProjecto=134327&idElemConcurso=7773). She is Researcher at the Centre of Pharmacology and Chemical Biopathology (U38/FCT) and Member of FMUP of the PhD Programs in Metabolism Clinical and Experimental and on Neuroscience: Clinical Neurosciences, Neuropsychiatry and Mental Health. She belongs to the teaching staff of the Curricular Unit “Medical Humanities”.

Anne Wilhelmina Saskia Rutjes -‐ University of Bern

Dr. Anne W.S. Rutjes is a senior scienti'ic consultant working from Italy and is employed as a senior epidemiologist at the University of Bern in Switzerland. In the last 10 years, her publications focused on the methodology of diagnostic test accuracy (DTA) studies and systematic reviews of both DTA studies and intervention studies. Dr Rutjes was one of the founders of QUADAS and QUADAS-‐2, a tool to assess the methodological quality of DTA studies, evaluated the impact of the STARD initiative for the improved reporting of diagnostic test accuracy studies, is author in the Cochrane Handbook for systematic reviews of DTA studies and continues to lecture epidemiological concepts, principles and methods at the Universities of Bern, Modena and Chieti.

Alessandro Squizzato -‐ University of Insubria MD PhD, he is Assistant Professor in Internal Medicine at University of Insubria, Varese, Italy. Head of the Varese Research Unit of the interuniversity Research Center ‘Centro Thomas C. Chalmers e Alessandro Liberati’ on systematic review methodology and dissemination of evidence-‐based medicine, member of the 'Research Center on Thromboembolic Disorders and Antithrombotic Therapies' of the University of Insubria and active reviewer of the Cochrane Collaboration.

Marco Taddia -‐ University of Bologna Marco Taddia was appointed Associate Professor of Analytical Chemistry at the University of Bologna in 1987. His scienti'ic production was focused on the analysis of industrial materials. He started his career doing chromatography and electroanalysis then he turned to the study of analytical atomic spectroscopy at the Imperial College (London). He also had a long-‐standing interest in the history of chemistry. He’s the current President of the "Gruppo Nazionale di Fondamenti e Storia della Chimica" (2014-‐2017) and of'icial representative of the Italian Chemical Society to the EuCheMS Working Party on the History of Chemistry. He's also Member of the Commission for the "Edoardo Amaldi” Center of Contemporary History of Science and XL (The National Academy of Sciences). He’s involved in the 'ield of scienti'ic vulgarization and Member of the Editorial Board of "La Chimica e l'Industria", the of'icial organ of the Italian Chemical Society.

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Module #3 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS Giuseppe ARMOCIDA L'integrità del medico e l'integrità nella ricerca: sviluppo storico Renzo PEGORARO Integrità nella ricerca: quale ruolo per i comitati etici Mario PICOZZI Ruolo della consulenza etica nella ricerca clinica Marco FERRARI Responsible research practice in pharmacogenetic studies Paolo CATTORINI Farmaci, etica e cinema

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Module #3 – HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS

L'INTEGRITÀ DEL MEDICO E L'INTEGRITÀ NELLA RICERCA: SVILUPPO STORICO Giuseppe Armocida

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH Promoting the responsible conduct of biomedical research

10th-‐14th November 2014, University of Insubria

Varese – Italy

L'INTEGRITÀ DEL MEDICO E L'INTEGRITÀ NELLA RICERCA: SVILUPPO STORICO Giuseppe Armocida

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INTEGRITÀ NELLA RICERCA: QUALE RUOLO PER I COMITATI ETICI Renzo Pegoraro



Varese – Italy

Prof. Rev. Renzo Pegoraro Varese November 14, 2014

RESEARCH ETHICS RESEARCHER’S ETHICS

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Research Ethics   Moral justification of human experimentation   Opportunities and limits in biomedical

experimentation: dignity of the human being

U-litarian Perspec-ve (L. Eisenberg) →  To obtain, by promoting biomedical progress, important benefits to the society of today and tomorrow →  “social imperative” Objections: −  Difficult to foresee future benefits of biomedical research; −  How to evaluate the risk-‐benefit ratio J. Rawls: “The ability to justify institutions, based on the fact that the sacrifices of some are offset by an overall greater good, can be useful but it is unjust”

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Contractual perspec-ve (R. Veatch) →  Free and conscious agreement through a cooperation

“pact” →  Centrality of the “informed consent”

Objection: −  Is the “informed consent” sufficient? −  Which relationship between patient and researcher?

Perspec-ve of Solidarity (A. Fagot-‐Largeault) →  Mutual involvement between researcher and

patient → Reference to “other/s” who will benefit from the results Conditions: −  Political −  Anthropological −  Institutional

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BIOMEDICAL RESEARCH We need to reflect on: §  Inherent requirement for medicine §  Need for methodological correctness and result reliability §  Guarantees for the protection of those involved §  Benefits for the community §  Economic aspects and use of resources §  Social control and regulation

Ethical perspec-ve −  From experimentation on persons to experimentation

with persons 1.  Respect of dignity and integrity of the human person 2.  Researcher’s responsibility and commitment 3.  Social dimension and solidarity 4.  Clear and effective rules 5.  Trust in Researchers and Institutions

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NEED FOR REGULATION among ethics – deontology -‐ law I. 

Some important Documents

II.  Ethics Committees /IRBs III.  Informed consent

I. SOME GUIDANCE DOCUMENTS FOR CLINICAL TRIALS NURNBERG CODE (18th W.M.A.) HELSINKI DECLARATION -‐ Helsinki BELMONT REPORT Directive no. 91/507/CEE on “Good Clinical Practice” WHO/CIOMS Internaitonal Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva) 2001  (October 3-‐4) IBC (UNESCO) 2003  International Conference on Harmonization Guidelines for “Good Clinical Practice” (ICH Harmonized Tripartite Guideline) -‐ European Council Convention on Human Rights and Biomedicine (Oviedo, April 4, 1997) 2001/03 Directive 2001/20/CE European Parliament and Council (D.I. no. 211; G.U. 9/8/03) 2002  NEW WHO/CIOMS INTERNATIONAL ETHICAL GUIDELINES FOR BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (Geneva) 2009  HELSINKI DECLARATION – Seoul 2012 (64th W.M.A) HELSINKI DECLARATION – FORTALEZA (BRASIL) 2014 REGULATION UE n. 536/2014 of the European Parliament and the Council 1947  1965  1981  1995  1997 

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Helsinki 2013  Art. 7.:

Medical research is subject to ethical standards that promote and ensure respect to all human subjects and protect their health and rights.

Helsinki 2013  Art. 8.:

While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.

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Helsinki 2013   Art. 23.:

“The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standarts but these must not be allowed to reduce or eliminate any of the protections for research subject set forth in this Declaration”.

EUROPEAN COUNCIL CONVENTION ON HUMAN RIGHTS AND BIOMEDICINE (Oviedo, April 4, 1997)

Art. 16 Research on a person may only be undertaken if all the following conditions are met: 1.  there is no alternative of comparable effectiveness to research on humans; 2.  the risks which may be incurred by that person are not disproportionate to the potential benefits of the research; 3.  the research project has been approved by the competent body….. after multidisciplinary review of its ethical acceptability; 4.  The persons undergoing research have been informed of their rights and the safeguards; 5.  Written consent.

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COUNCIL OF EUROPE CONVENTION   Focus on the human person and human rights

perspective

  Guarantees for the protection of the human being   Concept of “minimal risk” for “non-‐therapeutic”

research on incompetent individuals (cf Additional Protocol, 25/01/2005)

GCP – GOOD CLINICAL PRACTICE (1997; 2001) GOALS 1.  To ensure the respect of human rights 2.  To ensure the quality and reliability of data

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RESEARCH ETHICS COMMITTEE

(1)

A) Good Clinical Practices (1997) Ethics Committee/IRB: Independent Ethics Committee (IEC)“ An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals, and non-‐ medical members, whose responsability it is to ensure the protection of the rights, safety and well-‐being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/ providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

RESEARCH ETHICS COMMITTEE

(2)

The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline. (1.27)

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RESEARCH ETHICS COMMITTEE B) Directive 2001/20/CE European Parliament and Council -‐  Ethics Committee/IRB: “ethics committee”: an independent body in a Member State, consisting of healthcare professionals and non-‐medical members, whose responsability it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent”.

RESEARCH ETHICS COMMITTEE C) HELSINKI 2013 -‐  Ethics Committee/IRB: “The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standarts but these must not be allowed to reduce or eliminate any of the protections for research subject set forth in this Declaration. (art. 23)

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RESEARCH ETHICS COMMITTEE D) REGULATION EU 2014 “Ethics Committee means an independent body established in a Member State in accordance with the law of that Mambers State and empowered to give opinions for the purposes of this Regulation, taking into account the viws of laypersons, in particular patients or patiens organisations”. (art. 2 -‐ § 11)

Experimenta-on: Open ques-ons 1.  2.  3.  4.  5.  6.  7. 

Biostatistics setting of trials are often deficient Evaluating the innovative aspect of therapy compared to the traditional one Correctness and completeness of information; in view of the real consent ot the patient People not able to give their consent and vulnerable people Evaluation of the cost-‐benefit ratio for the subjects involved Insurance coverage for possible damages Guarantees of confidentiality with respect to the data learned from the research, for the protection of the patient

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Experimenta-on: Open ques-ons Use and justification of placebo “Competitive recruitment” 10.  Publication of the studies’ results 11.  “Non profit”/independent studies 12.  Continuation of treatment for patients who had benefit from study 13.  Other areas of experimentation/research: genetics, surgical, procedures, pathophysiology, stem cells 8.  9. 

RESEARCHER’S ETHICS 1.  To develop some basic moral virtues:

-‐ rigor -‐ transparency -‐ loyalty -‐ humility -‐ prudence -‐ consistency -‐ courage -‐ respect

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RESEARCHER’S ETHICS 2.  Issue about the relationship among

transparency and confidentiality / secrecy, personal initiative and collective interest.

4.  Declaration, management, overcoming of

possible interest conflicts (career, prestige, economic benefit, ….)

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RUOLO DELLA CONSULENZA ETICA NELLA RICERCA CLINICA Mario Picozzi



Varese – Italy

RESEARCH ETHICS CONSULTATION

Mario Picozzi Insubria University

ETHICS CONSULTATION  Ethics consultation is a set of services provided by an individual or a group in response to questions from patients, families, surrogates, health care professionals, or other involved parties who seek to resolve uncertainty or conflict regarding value-laden concerns that emerge in health care

 Core competencies for healthcare ethics consultation, 2nd ed., 2011

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ETHICS CONSULTANT  A particular ethics consultan may specialize in  - clinical ethics  - organizational ethics  - professional ethics  - business ethics  - education ethics  - research ethics

WIKIPEDIA RESEARCH ETHICS CONSULTATION

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THE UNIVERSITY OF CHICAGO

UNIVERSITY OF IOWA

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RESPONSIBLE RESEARCH PRACTICE IN PHARMACOGENETIC STUDIES Marco Ferrari



Varese – Italy

RESPONSIBLE RESEARCH PRACTICE IN PHARMACOGENETIC STUDIES MARCO FERRARI

CENTER FOR RESEARCH IN MEDICAL PHARMACOLOGY

SINGLE NUCLEOTIDE POLYMORPHISM The most common type of genetic variations among people (90% of all polymorphisms) are Single Nucleotide Polymorphism (SNP, pronounced snip; plural snips) is a DNA sequence variation occurring commonly within a population (> 1%) in which a single nucleotide between individuals.

differs

SNPs CARACTERISTICS • SNPs are mostly biallelic polymorphisms and are inherited in a Mendeleian way. • SNPs can cause silent, harmless, harmful or latent effects. • Most commonly SNPs are found in the DNA between genes, in noncoding region, having non effects on gene expression and/or functions. • The remaining SNPs occur in the regulatory or coding regions. They could alter gene expression or protein functions, which in turn could influence a person’s phenotype.

• Susceptibility to environmental factors (such as toxin). • Risk of developing particular disease. • Individual response to drug.

http://www.pgx.vcu.edu/index.htm

Pharmacogenomics studies will facilitate delivering genomic biomarkers contribution to truly personalised medicines and facilitate early detection.

Current clinical practices

Pharmacogenetics

…

…

NON-REPRODUCIBILITY IN PHARMACOGENETIC STUDY: WHY? • True heterogeneity, e.g., ethnicity, differences in effect between populations of differing ancestry. • Violation of Hardy–Weinberg equilibrium. • Limited knowledge of pharmacokinetic and pharmacodynamic pattern involved in drugs action. • Incomplete functional characterization of SNPs in genes coding for proteins involved in the drugs action. • Low minor allele frequencies/small effect size.

NON-REPRODUCIBILITY IN PHARMACOGENETIC STUDY: WHY? • Bias in study design, e.g evaluation response based on intermediate outcomes, etc. • Selection bias, e.g. diagnostic criteria, subjects characteristics, etc. • Measurement bias, data irregularities, e.g., poor methodological quality in small studies; artifacts, (e.g., differences due to effect measure employed). • Publications bias, e.g. multiple publication of small studies or unpublishing of negative or non significant findings.

NON-REPRODUCIBILITY IN PHARMACOGENETIC STUDY: WHY? • Bias in study design, e.g. evaluation response based on intermediate outcomes, etc. • Selection bias, e.g. diagnostic criteria, subjects characteristics or phenotype definitions. • Measurement bias, data irregularities, e.g., poor methodological quality in small studies; artifacts, (e.g., differences due to effect measure employed). • Publications bias, e.g. multiple publication of small studies or unpublishing of negative or non significant findings.

BIAS IN STUDY DESIGN • Consideration of multiple markers, functionality, and significance e.g. contribution from SNPs of CYP2C19 and WKORC1 for warfarin metabolisms. • Evaluation of treatment response based on surrogate markers or intermediate outcomes, rather than long-term hard clinical endpoints. Surrogate and intermediate outcomes may still be useful to document, but they may not be very informative clinically

NON-REPRODUCIBILITY IN PHARMACOGENETIC STUDY: WHY? • Bias in study design, e.g.evaluation response based on intermediate outcomes, etc. • Selection bias, e.g. diagnostic criteria, subjects characteristics or phenotype definitions. • Measurement bias, data irregularities, e.g., poor methodological quality in small studies; artifacts, (e.g., differences due to effect measure employed). • Publications bias, e.g. multiple publication of small studies or unpublishing of negative or non significant findings.

NON-REPRODUCIBILITY IN PHARMACOGENETIC STUDY: WHY? • Bias in study design, e.g.evaluation response based on intermediate outcomes, etc. • Selection bias, e.g. diagnostic criteria, subjects characteristics or phenotype definitions. • Measurement bias, data irregularities, e.g., poor methodological quality in small studies; artifacts, (e.g., differences due to effect measure employed). • Publications bias, e.g. multiple publication of small studies or unpublishing of negative or non significant findings.

MEASUREMENT BIAS • Pre-analytical aspects (sampling, storage, DNA extractions) • Choice of technologies/GBM used (Rationale) • Reproducibility of technologies used (Validations). • Management and conservation of the biological material and results (transparency).

MEASUREMENT BIAS • Pre-analytical aspects (sampling, storage, DNA extractions) • Choice of technologies used (Rationale) • Reproducibility of technologies used (Validations). • Management and conservation of the biological material and results (transparency).

MEASUREMENT BIAS • Pre-analytical aspects (sampling, storage, DNA extractions) • Choice of technologies/GBM used (Rationale) • Reproducibility of technologies used (Validations). • Management and conservation of the biological material and results (transparency).

CHOICE OF TECHNOLOGIES/GBM USED

DIRECT SEQUENCING

RFLP-PCR

HRM

RT-PCR

TAQMAN

MEASUREMENT BIAS • Pre-analytical aspects (sampling, storage, DNA extractions) • Choice of technologies used (Rationale) • Reproducibility of technologies used (Validations). • Management and conservation of the biological material and results (transparency).

TEST VALIDATIONS:

ACCURANCY

• Repeated determinations, to ensure that a single observation is not accidental. • Tests of coded specimens, positive and negative control DNA samples should be used. i.e. tubes with water and tubes containing e.g. genomic DNA from subjects’ known to have different genotypes of the SNPs being analysed: homozygous for each of the allele and heterozygous for both alleles. In case of rare alleles where appropriate DNA standards are unavailable, proper DNA sequencing analysis has to be done in order to validate the method for SNP detection.

TEST VALIDATIONS: INTERMEDIATE

PRECISION

Describes the within-laboratory variations of repeat test results with one test system: • different day • different analyst • different equipment

TEST VALIDATIONS: REPRODUCIBILITY Is the inter-laboratory precision, which may be determined as the variations of the repeat test results for one test system in different laboratories.

MANAGEMENT AND CONSERVATION OF THE BIOLOGICAL MATERIAL AND RESULTS (TRANSPARENCY)

2, November 2007, EMEA/CHMP/ICH/437986/2006

"Here's my sequence...”

THANK YOU FOR YOUR ATTENTION

New Yorker


FARMACI, ETICA E CINEMA Paolo Cattorini



Varese – Italy

1 First Insubria International School in Methodology, Ethics and Integrity in

Biomedical Research, State Univ. Insubria, Varese, Italy (Nov. 12, 2014). Paolo M. Cattorini, Professor of Bioethics, Insubria University.

Drugs, Ethics and Cinema. (Abstract)

Premise. Ethics rationally justifies value-‐attitudes and positions. Ethics needs narratives to implement its moral suasion, because general rules, prima-‐facie principles and intellectual theories have their roots in background stories-‐of-‐origin, that philosophers contribute to clarify, analyse, interpret and apply to different cases and situations1. “What does it mean, persuasion? When Jane Austen wrote her last complete novel [Persuasion], it could mean two different things. A firm belief, or else the process of persuading someone to think 2 differently, and of being persuaded” . Both meanings figure significantly in the job of applying ethics, because they represent the actually practised moral/morals and the critical reflection upon them, in order to confirm or modify one’s convincements or habits.

Imperilled Principles of Biomedical Ethics. 1. Moral Integrity of Health Care Professions and of Biomedical Researchers. “Health care professionals have a clear responsibility to act in accordance with the ethical mandates of their professions and reasonable standards of practice. One of their obligations is to respect the considered choice of the patient or the patient’s surrogate and to affirm the values of compassion and human dignity […] Some health care professionals have personal commitments to ethical or religious mandates that raise issues in the course of caring for patients. A health care professional is not required to violate such personal commitments”3. The scientific practice is autonomous and independent with regard to its inherent aim (to expand and deepen the scientific knowledge); but it is submitted to an ethical evaluation with regard to its means, conditions, circumstances and foreseeable consequences4. A German medical experimenter, working in Berlin (1923), discloses his results to a layperson, a circus tumbler. “People does anything for some money and a decent meal”. 1

See our articles, “Aesthetics in Ethics: Narrative and Theoretical Dimensions of Moral Evaluation”, Eubios. Journal of Asian and International Bioethics, 19, March 2009, pp. 47-‐53; “The Winter of Clinic? Advanced Ethical Dilemmas for an Advanced Medicine”, Eubios Journal of Asian and International Bioethics, v. 20 (6), Nov. 2010, pp. 183-‐190; “Shall I Become a Zombie? Stories of Illness, Ethical Dilemmas and Visions of Society”, Medicina nei Secoli. Arte e Scienza. Giornale di Storia della Medicina – Journal of History of Medicine, 2009, v.21, n.3, pp. 1017-‐ 1036; “Movies on Bioethics. A Double Review and Some Steps Forward”, The Journal of Aesthetic Education, (Univ. Illinois Press), v. 46, n.2, Summer 2012, pp. 111-‐121; “Doing Justice to Bioethics: The Role of Cinema”, Eubios Journal of Asian and International Bioethics, v. 23 (4) July 2013, pp. 147-‐154; ”Clinical Ethics as Applied Aesthetics”, Journal of Aesthetic Education, (Univ. Illinois Press) v. 48, n.2, Summer 2014, pp. 16-‐35. About the notion “stories-‐of-‐origin” we endorse W.T. Reich’s thesis expressed in “Alle origini dell’etica medica: mito del contratto o mito di cura?”, in P.M. Cattorini – R. Mordacci, Eds., Modelli di medicina. Crisi e attualità dell’idea di professione, Milano, ESU, 1993, pp. 35-‐60. 2 Elaine Jordan, Introduction to J. Austen, Persuasion (1817), Ware – Hertfordshire, Wordsworth Ed., 2000, p. V. 3 The Hastings Center, A Report by, Guidelines on the Termination of Life-‐Sustaining Treatment and the Care of the Dying, Bloomington & Indianapolis, Indiana University Press, 1987, pp. 19-‐20. 4 E. Agazzi, “Autonomia e responsabilità della scienza”, in P. Cattorini, a cura di, Scienza ed etica nella centralità dell’uomo, Milano, FrancoAngeli, 1990, pp. 135-‐146.

2 Film: I. Bergman, L’uovo del serpente – Das Schlangenei, Germania Ovest – Usa 1997 (1 h 41’ to 1h 51’ 50’’)

2. Nonmaleficence. “One ought not to inflict evil or harm (what is bad) […] The duty of nonmaleficence encompasses not only actual harms but also risks of harm. Risks vary according to the probabilities and the amounts of harm”5. First, do not medically treat the healthy persons! The case of psychiatry and some debatable objections raised: the abuse of DSM, 5th edition; the diagnostic inflation; the biological bias of the nosology; the direct pharmaceutical advertising to consumers and general practitioners; requests by some health insurance companies; the social need of justifying a stigma through scientific categories6. Film: S. Savino, ADHD – Rush Hour, Italia, 2012 (doc., 80 min., Microcinema-‐Distribuzione) (20’20’’ to 24’ 42’’)

3. Justice. Chose and defend just, equal and transparent criteria of recruitment! “Ideally, the subject should give his consent freely, under no duress whatsoever. The facts are that some element of coercion is instrumental in any investigation-‐ subject transaction. Volunteers for experiments will usually be influenced by hopes of obtaining better grades, earlier parole, more substantial egos, or just mundane cash. These pressures, however, are but fractional shadows of those enclosing the patient-‐ subject. Incapacitated and hospitalized because of illness, frightened by strange and impersonal routines, and fearful for his health and perhaps life, he is far from exercising a free power of choice when the person to whom he anchors all his hopes asks [his help]”7. What about transforming unaware homeless people into research heroes? Put yourself in the distressing condition of a tetraplegic patient, longing for a new neurological treatment. Shall you remain a moralist? Film: M. Apted, Extreme Measures – Soluzioni estreme, Usa/GB 1996 (1h 19’ 10’’ to 1h 25’ 10’’).

4. Autonomy. Is the main function of informed consent the protection of individual autonomy, also in developing countries? What kind of information disclosure and comprehension is required, when the weak cultural tools and the high level of poverty expose vulnerable people to their bodily exploitation by drug-‐market pressures? The case of an antibiotic testing in Africa (1996), which inspired (according to the comment by B. Goldacre -‐ later quoted, p. 130 -‐ who recalls the previous novel written by John le Carré) the plot represented in a 2005 movie. Film: F. Meirelles, The Constant Gardener, Usa/Gb 2005 (1h 37’ 00’’ to 1h 41’ 30’’)

You can read, among others DVD-‐film closing credits (such as the usual -‐ by paraphrasing -‐ “…incidents portrayed are all fictitious…similarities to history and actuality …are…coincidental and unintentional… ”), the following statement by J. le Carré: “Nobody in this story, and no outfit or corporation, thank God, is based upon an actual person or outfit in the real world, but I can

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T.L. Beauchamp – J.F. Childress, Principles of Biomedical Ethics, New York – Oxford, Oxford Univ. Press, 1983 (2 Ed.), pp. 109-‐110. P.M. Cattorini, Bioetica. Metodo ed elementi di base per affrontare problemi clinici, Milano, Elsevier, 2011 (4th Ed.), cap. 4: “La sperimentazione clinico-‐farmacologica e il consenso”, pp. 83-‐100. 6 A. Frances, Primo, non curare chi è normale. Contro l’invenzione delle malattie, Torino, Bollati Boringhieri, 2013 (Saving Normal. An Insider’s Revolt Against Out-‐of-‐Control Psychiatric Diagnosis, “DSM – 5”, Big Pharma, and the Medicalization of Ordinary Life, 2013). 7 F.J. Ingelfinger, “Informed (but Uneducated) Consent”, N.E.J.M., v. 287, n. 9, Aug. 31, 1972, pp. 465-‐466.

3 tell you this, as my journey through the pharmaceutical jungle progressed, I came to realize that, by comparison with the reality, my story was as tame as a holiday postcard”.

See also: D. Mohan Gray, Fire in the Blood, Doc., India e GB 2012 See also: Il colore del sangue (Miss Evers’ Boys), directed by Joseph Sargent, Usa 1997, about the famous Tuskegee study (Alabama), denounced by H.K. Beecher, N.E.J.M., 1966 (conducted since 1932).

5. Beneficence. Prevent or remove evil! Do or promote good! But what kind of evil /good? The seduction of enhancement leads to prescribe drugs to increase psycho-‐ physical performances.

“Some would argue that it is inconsistent, and even hypocritical, for the government bodies of sports to attempt to justify a ban [about doping] by appealing to the athlete’s well-‐being. There are many training practices, and indeed many sports, that carry a far greater likelihood of harm to the 8 athlete than does the controlled use of steroids” . “It is important to randomize from the very first patient not only to protect future patients but also to protect the first patients, who should have a chance to fall into the control group when the new treatment may well be ineffective because of the inexperience of the person who is applying it. The control patient can always be removed from that group and placed in the experimental group if and 9 when the new treatment seems to be superior to the old” .

“It doesn’t change you; it just make you be who you actually are”. Film: S. Soderbergh, Effetti collaterali (Side Effects), Usa 2013 (22’35’’to 27’15’’) Conclusions and Proposals. Rethink the meaning of common words, like good science, and the role of regulatory agencies10 (for instance, those in charge of the post-‐marketing surveillance)! We ethicists should thoughtfully respond to the suspicion raised by a British medical journalist… Il sospetto che, anche nei nostri Paesi cosiddetti avanzati, i comitati etici e le università ci abbiano “tradito”, si alimenta anche per la convinzione che “nascondere i risultati dei trials clinici è immorale, per la semplice ragione che l’occultamento dei dati espone i pazienti a danni non necessari ed evitabili” e fraintende la motivazione altruistica con cui molti pazienti decidono di fungere da soggetti di sperimentazione11. Sulle “clausole bavaglio”, una raccomandazione ai comitati etici è stata formulata come segue: “A nessuno dovrebbe essere consentito di condurre trials su esseri umani se, al momento, come responsabile di un progetto d ricerca, sta bloccando la pubblicazione dei dati di un trial a più di un anno dalla sua conclusione […] Nessun trial 12 dovrebbe essere autorizzato senza una solida garanzia di pubblicazione entro un anno dalla conclusione” (ivi, p. 58).

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T.H. Murray (revised by A.J. Schneider), “Sports, Bioethics of”, S.G. Post, Ed. in Chief, Enc. Bioethics, 3 Ed., Farmington Hills, Macmillan-‐Gale, 2004, p. 2463. 9 T.C. Chalmers, “The Ethics of Randomization as a Decision-‐Making Technique, and the Problem of Informed Consent”, in T.L. Beauchamp – LeRoy Walters, Eds., Contemporary Issues in Bioethics, 2nd Ed., Belmont, Wadsworth Pub. Co., 1982, pp. 538-‐541. 10 S. Garattini – V. Bertelè, “Rosiglitazone and the Need for a New Drug Safety Agency”, B.M.J., Oct. 6, 2010, 341, 7776, c5506. 11 B. Goldacre, Effetti collaterali, Milano, Mondadori, 2013 (Bad Pharma. How Drug Companies Mislead Doctors and Harm Patients, 2012), p. 49. 12 Ivi, p. 58. See also B. Goldacre, La cattiva scienza, Pearson Paravia Bruno Mondadori, 2009 (Bad Science, 2008).

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After the suicide of a biomedical researcher, the Vice-‐President of a drug company (experimenting with an Aids vaccine) discovers both a scientific fraud and an insider trading affair. How much courage is needed to notify timely the ethics commission? Film: S. Lee, Lei mi odia. She hate me, Usa 2004 (12’20’’ to 16’20’’)