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Accidents During Clinical Trials Houria Chikhi Juliette Paillard 27 février 2017 Séminaire Réglementaire Clémence Patte Augustine Screpel 1 Key points of CT Regulation TGN-1412 (2006) BIA 10-2474 (2016) Conclusion 2 Key Points of Clinical Trials Regulation 3 Life Cycle of Medicine 4 Preclinical Studies ICH M3: “Note for guidance on non-clinical safety studies for the conduct of human CT and MA for pharmaceuticals” ICH S6: “Preclinical safety evaluation of biotechnology-derived pharmaceuticals” Aim : to determine the 1st dose to administrate to humans Pharmacodynamic MOA, target affinity, primary and secondary effect(s) Pharmacokinetic ADME Acute -4 to 5 doses -observation: 14 days -mice+rats Subacute -2 species, 2 genders, several doses -90 days Chronic -2 species, 2 genders, several doses -6 to 12 months Toxicology -DL0, MTD, LD100, LD50 -Reprotoxicity, cancerogenesis, mutagenesis 5 NOAEL or MABEL ? NOAEL MABEL • Non Observable Adverse Event Level. • Minimal Anticipated Biological Effect Level • Based on toxicology • Justify based on pharmacology • Dependant of animal species • Include anticipation duration effect 6 Clinical studies 1) UE Legislation • Directive 2001/20/CE: Applied in 2004(UK) and 2006 (FR) Requirements : Protection of trial participants Competent authority + Ethic Committee Approval Safety Requirements Reports Registration of the Clinical Trial (EudraCT) Reinforcement people protection involved in Clinical Trial • Regulation 536/2014 : Applicable in 2018 7 Clinical Studies 2) FR legislation • Law 2012-300 = Loi Jardé with decree n° 2016-1537 of 16/11/2016 3) UK legislation • SI 2004/1031 The Medicines for Human Use (CT) Regulations 2004 with numerous amendments. 8 Clinical Trial : Actors SPONSOR • Ethic Competent Authorities Sponsor: an individual, company, institution or organisation Committee CRO which takes responsibility for the initiation, for management and for setting up the financing of the CT. Authorisation the Favorable Opinon • • Contract ResearchIndependent Organization (CRO): A person or an Ethic Committee: body. Responsible to protect organization contracted the ofsponsor perform one or the rights, safety and wellby being human to subjects involved more sponsor’s trial-related duties andof functions. in CT,ofand to provide public assurance that protection 9 Clinical Trial : Actors (3/3) SPONSOR Competent authorities CRO Investigator: an individual responsible for the conduct of a CT at a CT site. Ethic Committee Favorable Opinon Authorisation Investigator Start of CT 10 TGN-1412 13 Actors Role Name Location Sponsor Germany Manufacturer Germany CRO Investigator Northwick-UK Competent Authority London-UK 14 1. The study TGN-1412 15 Molecule • Humanized IgG4κ mAb • Superagonist binding CD28 16 Medical need Autoimmune disease: Cellular mechanisms Autoreactive CD4+ Th lymphocytes CD4+ Treg and CD8+ supressor Loss of selftolerance Dysregulated signaling 3% people worldwide 75% women Comparable structure selfAG foreign molecules 17 Medical need B Cells Chronic lymphocytic leukemia: • Leukemic B cells accumulation • T cell abnormalities TOLERANCE VS LEUKEMIC B CELLS 18 Preclinical studies • Mice : Healthy mice : to determine and select Treg Unwell mice : to determine the DME • Monkeys Safety and toxicology studies done on Rhesus and Cynomolgus Monkeys TGN-1412 induces activation and expansion of T cell only in Cynomolgus Monkey → studies conducted on them 19 Preclinical studies • NOAEL: 50mg/Kg per week (4 weeks max) Determined by a repeat dose study : IV - 5 doses up to 50 mg/Kg TGN-1412 well tolerated up to 50mg/Kg • PK : Half life : 8 hours (Monkeys) Full removal : 1 month 20 How the started dose was calculated ? Security Factor /10 •50 mg/kg •Non Observed Adversed Event HED •Human Equivalent dose •16 mg/kg NOAEL Surface area allometric correction factor •Maximum Recommended Starting Dose •1,6 mg/Kg MSRD Starting dose • 0,1 mg/kg • First human dose Safety Margin 21 Design • • • • • • • Phase I Single-centre Double-blind Randomized Placebo Controlled Single escalating dose study To assess safety, pharmacokinetics, pharmacodynamics and immunogenicity of TGN-1412 22 Design Only Men (18-40 yo) 0,1 mg/kg 0,5 mg/kg 2,0 mg/kg 5,0 mg/kg Dose escalation schema x4 TGN-1412 Placebo 23 2.What happened ? TGN-1412 24 Chronology Multiorgan failure Patient 6 Start of Clinical Trial 13th March 2006 Multiorgan failure All patients Within 5 hours “Cytokin storm” Incident reported to MHRA 14th March 2006 Within 20 hours + Methyl Prednisolone ICU 25 What happened ? 26 3. Investigations TGN-1412 27 Inspections: - Dosing error ? - Error in the formulation or dilution ? - Contamination ? - Unknown biological effect ? Disapproved hypothesis • Appointment of an ESG (Expert Scientific Group) 28 ESG “Pre-clinical development studies performed with TGN-1412 did not predict a safe dose for use in humans, even though current regulatory requirements were met” In vitro assays : dose of TGN-1412 given to volunteers was close to the maximum immunostimulatory dose. • “Differences of up to 4% existed in the amino-acid sequences of the C”D loop of CD28 receptor in rhesus and cynomolgus with that of humans” 29 OKT3 case • With OKT3, similar effects on animals and humans to those observed with TGN-1412 • In brochure: “Precautions” “Cytokine release: (…) The anti-CD3 monoclonal antibody OKT-3, elicits a “cytokine-storm” characterized by an increase in systemic inflammatory mediators. In the unlikely event that TGN-1412 also induces massive cytokine release, appropriate counter-measures must be taken.” 30 Investigator’s brochure failure • “100% homology exists between the CD28 TGN1412 binding site in human beings and monkeys, restricted to the so-called C”D loop.” => However, no sequence comparison was included in the disclosed information. • Only provides information on the affinity of TGN1412 to the human CD28 molecule (1·88×10−9 mol/L), not for its monkey counterpart. 31 Doses administered and timing Subjects 1 2 3 4 5 6 Body weight (kg) 84.4 69.9 88.5 82.4 72.1 81.8 Dosing TGN1412 (mg) 8.4 6.8 8.8 8.2 7.2 8.2 Dosing time (AM) 08:00 08:20 08:30 08:40 08:50 09:00 Only 10 minutes between administrations 32 4. Measures/Recommandations TGN-1412 33 Management and reduction of risk : • FIH trials of mAb or new biologic would not be sanctioned by the MHRA without having received the benefit of additional expert opinion 34 ESG Experts Recommandations to optimize security : • Assessment of 1st in man trial should be sciencesbased made and a justified on a case by case basis on individuals • Determining and administering the initial doses in man • Structured approach needed for the evaluation of pre-clinical and clinical experiments 35 EMA New regulatory environment : “Guideline on strategy to identify and mitigate risk for first in-man Clinical trial with investigational medicinal products” •Conduct of the CT : case by case science driven approach •Estimating FIH starting doses and dose escalation •Understanding and projecting the likely effects of the first pharmacologically active dose administered to humans. 36 What about today ? - TeGenero went into insolvency in 2007 - TGN1412 commercials rights were acquired by a Russian Company - TAB08 - Indication : Rheumatoid Arthritis - Phase II “A sophisticated product could be destroyed by inadequate development.”-Adam Cohen 37 BIA 10-2474 38 Actors Role Name Location Sponsor Portugal Manufacturer Portugal CRO Investigator RennesFrance Competent Authority Paris-France 39 1.The study BIA 10-2474 40 Molecule : BIA 10-2474 Inhibitor of fatty acid amide hydrolase (FAAH) Indication : Neuropathic Pain (According to Bial , Reversible Inhibitor) 41 FAAH : Fatty Acid Amid Hydrolase • Serine hydrolase with an unusual SerSer-Lys catalytic triad • After release of Anandamid, cause its hydrolysis • Anandamid + H20 ← → arachidonic acid + ethanolamin 42 Anandamid - ⅓ Endocannanabinoid - Inhibition by FAAH → Anandamid degradation inhibition → Anandamid - High affinity for CB1 receptor and low affinity for CB2 Anandamid - Retrograde action 43 Mechanism of action 44 Preclinical studies Species NOAEL (mg/kg) NOEL (mg/kg) Mice 100 25 Rats 30 10 Dogs 50 20 Monkeys 100 75 4 species instead of 2 45 Preclinical studies 46 Protocol • • • • • • Phase I Single-centre Double-blind Randomized Placebo-controlled Including additional FI and PD part To assess safety and tolerability of BIA 10-2474 after SAD and MAD To characterize the PK and PD and assess several potential PD effects. 47 Dose escalation SAD Cohort • 5 fold increase from the first dose 0,25 mg to the second • 2-fold until 100 mg MAD Cohort Once daily D1 to D10 Dose levels: after evaluation of safety , tolerability and available PK results of previous of SAD and MAD dose groups • PK and PD assessment • • 48 Inclusion/Exclusion Criteria Inclusion Criteria • Male or female (only male for the PD part) • BMI between 19 and 30 kg/m² • Healthy, negative tests for virus • Negative screen for alcohol and drugs Exclusion criteria • Subjects with surgery history, • History of hyperemesis, atopy, alcoholism or drug abuse • Significant infection or known inflammatory process 49 2. What happened ? BIA 10-2474 50 Chronology 1st subject declared brain dead 1st subject was hospitalized 06/01 50 mg dose Cohort 5 10/01 11/01 1st subject slips into coma Study stopped 12/01 Authorities notified 13/01 5 subjects were hospitalized 14/01 17/01 1st subject died 51 3. Authorities Investigations BIA 10-2474 52 IGAS Cohort 50mg « The participants weren’t protected enough » 3 importants failures : 1. Failure to provide information to other volunteers and to confirm their consent. 2. Responsibility for failing to halt the trials after the first hospitalisation 3. Delay in informing the ANSM. 53 Appointment of TSSC (Temporary Specialized Scientific Committee) • On BIA 10-2474 Cohort 50mg • On clinical data and MRI of healthy volunteers Other cohorts 54 TSSC’report BIA 10-2474 « Accident clearly linked to the tested molecule » • About the molecule : low efficiency, low specificity and concentration-effect curve steep • Molecule capacity to set other cerebral structure off target • High risk molecule with minor interest Important role of the dose escalation in the accident Cohort 50mg 55 TSSC Review of clinical data & MRI • Nature and frequency of symptoms reported by volunteers receiving BIA10-2474 were unlike those seen in hospitalized volunteers in the 50mg cohort. Other cohorts Irrelevant 56 4. Transparency BIA 10-2474 57 CPP CPP Rennes A.Patat Rennes CPP’s Member A.Patat Biotrial Direction Member 58 Disclosure rules • Protocols and preclinical files are made available only well after the completion of the trial Data protection because of individual privacy requirements should be balanced with public health interests. 59 5.Scientific Discussion BIA 10-2474 60 Molecule Leaving group PF-04457845 Give the specificity Molecule Leaving group BIA 10-2474 Give a low specificity 62 Molecule • Low specificity • High reactivity • Covalent binding Evaluation failure 63 Preclinical failures • The preclinical dossier wasn’t made public • Brain damages in rats, mice and cynomolgus monkeys should have been investigated further. • 4 species • Maybe due to poor tolerance results in the 1st species • Bial : Delay in the clinical development 64 Dose calculation failures Highest dose: 100 mg High Risk Molecule Complete inhibition : 5mg MABEL ? 65 Pk and cumulative toxicity Covalent binding Non AE in SAD cohort Non linear PK for D>40mg ½ life increase with the dose elimination saturation Large distribution volume Graduation accumulation in the brain 66 Consequences: Off-target 200 Serine Hydrolase Molecule with Low specificity Off-target effects 9 metabolites3 with same intensity of action Brain lesions don’t match EC system 67 Protocol failures SAD MAD Disrepect of criteria Evaluation failure 68 6.Measures and recommendations BIA 10-274 69 Ministry of Health Biotrial must provide an action plan regarding 3 majors failures, within 1 month. Examination of the 90 CT records Enforcement of CTA conditions FR will continue its European action Requested the ad hoc authority to reinspect all authorized French research centers Any hospitalisation of a healthy volunteer in any CT = suspension of the CT 70 France Loi Jardé, Decree n°2016-1537 (16/11/2016): 71 France Loi Jardé, Decree n°2016-1537 (16/11/2016): 72 EMA New Phase I trial best practices paper Incorporating findings from ANSM and IGAS 2 workings groups : - Preclinical assessment and drug candidate - Clinical Design 73 7.Personal injuries compensation BIA 10-274 74 Compensation for personal injuries • Victims of drug disease link to CT Drug taken in CT Causal Link Existence of damages 75 2 ways of actions for victims Legal Process • Compensation by sponsor insurance. • Medical expertise by insurance • Healthcare product liability regim • Investigation by ANSM to determine liabilities Amicable Process • Compensation national solidarity . • Medical expertise by ONIAM (National Office for the Indemnisation of Medical Accidents) who suggested a compensation offer 76 Conclusion 77 Conclusion • CT are the only tools to provide the evidence needed for drug approval • Regulation are theoritical and administrative • To limit risks: Case by case approach 78 Thank you for your attention ! Questions ? 79 Bibliography (1) • • • • • • • • • • • • • • • • • TGN1412 Study Protocol TGN1412 Investigator Brochure From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis TGN1412: From discovery to disaster Cellular and molecular mechanisms of autoimmune disease The BIAL/Biotrial case of death of a human volunteer in the first-in-human study of BIA 10-2474: Are we missing the fundamentals? TGN 14-12 Interim Report. MHRA Expert Scientific Group on phase one clinical trials. Final report. Kenter et al, (2006). Establishing risk of human experimentation with drugs: lessons from TGN1412. The Lancet. 368 : (1387-1391) Clinical Study Protocol N° BIA-102474-101 Kerbrat et al (2016). Acute neurologic disorder from an inhibitor of fatty acid amid hydrolase. The New England Journal of Medicine. 375 :18 Guideline On Strategies To Identify And Mitigate Risks For First-Inhuman Clinical Trials With Investigational Medicinal Products Ref. EMEA/CHMP/SWP/28367/07 Enquete Sur Des Incidents Graves Survenus Dans Le Cadre De La Realisation D’un Essai Clinique, tomes 1 et 2, Mai 2016 First-in-Human Clinical Trials — What We Can Learn from Tragic Failures Sergio Bonini, M.D., and Guido Rasi, M.D. n engl j med 375;18 nejm.org November 3, 2016 Chronologie de l’évaluation et du déroulement de l’essai clinique promu par les laboratoires BIAL et réalisé par la société BIOTRIAL à Rennes, ANSM Janvier 2016 Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain The American Society for Pharmacology and Experimental Therapeutics 180257/3698355 JPET 338:114–124, 2011 80 Bibliography (2) • • • • • • • • • • • • • • https://www.parexel.com/company/news-events/press-releases/2006/mediaadvisory-update https://www.legifrance.gouv.fr/affichTexte.do;jsessionid=CC895B0A0D9DEA7EEDCC97 81ABEC7FBA.tpdila18v_1?cidTexte=JORFTEXT000025441587&dateTexte=20161117 http://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX%3A32014R0536 https://www.dlsweb.rmit.edu.au/set/LearningObjects/P3Project/module2/downloads/ 02_first_dose_in_humans.pdf https://scientistabe.wordpress.com/category/pharmacology/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964774/pdf/JYPharm-2-332.pdf https://www.clinicalleader.com/doc/france-tragedy-update-bial-biotrial-at-faultema-reviews-guidelines-0001https://www.clinicalleader.com/doc/france-tragedyupdate-bial-biotrial-at-fault-ema-reviews-guidelines-0001 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020770/ http://journals.sagepub.com/doi/full/10.1177/0192623311428481 https://www.bial.com/en/bial.1/history.5.html http://www.hma.eu/ermsfg.html GCP : https://www.gov.uk/guidance/good-clinical-practice-for-clinical-trials https://www.theguardian.com/society/2007/feb/17/health.lifeandhealth) https://jeanyvesnau.com/2016/01/30/essai-clinique-de-rennes-questions-sur-lescomites-de-protection-des-personnes-de-bretagne/ 81