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Accidents D uring Clinical Trials

Accidents D uring Clinical Trials. Houria Chikhi Juliette Paillard. Clémence Patte Augustine Screpel. 27 février 2017 Séminaire Réglementaire. 2. Key Points of Clinical Trials Regulation. Life Cycle of Medicine. 4. Preclinical Studies.

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Accidents D uring Clinical Trials

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  1. Accidents DuringClinical Trials Houria Chikhi Juliette Paillard ClémencePatte Augustine Screpel 27 février 2017 SéminaireRéglementaire

  2. 2

  3. Key Points of Clinical Trials Regulation

  4. Life Cycle of Medicine 4

  5. 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

  6. NOAEL or MABEL ? NOAEL MABEL • Non Observable Adverse Event Level. • Based on toxicology • Dependant of animal species • Minimal Anticipated Biological Effect Level • Justify based on pharmacology • Include anticipation duration effect

  7. Clinical studies • 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

  8. Clinical Studies 2) FR legislation • Law 2012-300 = Loi Jardéwith 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.

  9. Clinical Trial : Actors SPONSOR Competent Authorities Ethic Committee CRO • Sponsor: an individual, company, institution or organisation which takes responsibility for the initiation, for the management and for setting up the financing of the CT. Authorisation FavorableOpinon • Contract Research Organization (CRO): A person or an organization contracted by the sponsor to perform one or more of sponsor’s trial-related duties and functions. • Ethic Committee: Independent body. Responsible to protect the rights, safety and well being of human subjects involved in CT, and to provide public assurance of that protection

  10. Clinical Trial : Actors (3/3) SPONSOR Investigator: an individual responsible for the conduct of a CT at a CT site. Competent authorities Ethic Committee CRO Authorisation FavorableOpinon Investigator Start of CT

  11. TGN-1412

  12. Actors

  13. 1. The study TGN-1412

  14. Molecule • Humanized IgG4κ mAb • Superagonist binding CD28

  15. Medical need Autoimmune disease: Cellular mechanisms 3% people worldwide 75% women Autoreactive CD4+ Thlymphocytes Comparable structure self-AG foreign molecules CD4+ Treg and CD8+ supressor Loss of self-tolerance Dysregulatedsignaling

  16. Medical need B CellsChroniclymphocyticleukemia: • Leukemic B cells accumulation • T cell abnormalities TOLERANCE VS LEUKEMIC B CELLS

  17. Preclinical studies • Mice : • Healthy mice : to determine and select Treg • Unwell mice : to determine the DME • Monkeys • Safety and toxicologystudies done on Rhesus and Cynomolgus Monkeys • TGN-1412 induces activation and expansion of T cell only in Cynomolgus Monkey → studies conducted on them

  18. 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

  19. How the started dose was calculated ? Security Factor /10 Surface area allometric correction factor Safety Margin

  20. Design • Phase I • Single-centre • Double-blind • Randomized • Placebo • Controlled • Single escalating dose study •  To assess safety, pharmacokinetics, pharmacodynamics and immunogenicity of TGN-1412

  21. Design x4 Only Men (18-40 yo) Placebo TGN-1412 Dose escalation schema

  22. 2.What happened ? TGN-1412

  23. Chronology Multiorgan failure Patient 6 Multiorgan failure All patients Incident reported to MHRA Start of Clinical Trial 14th March 2006 13th March 2006 Within 5 hours Within 20 hours + Methyl Prednisolone “Cytokin storm” ICU

  24. What happened ?

  25. 3. Investigations TGN-1412

  26. Inspections: • - Dosing error ? • - Error in the formulation or dilution ? • - Contamination ? • - Unknown biological effect ? • Appointment of an ESG (Expert Scientific Group) Disapproved hypothesis

  27. ESG • “Pre-clinical development studies performed with TGN-1412 did not predict a safe dosefor 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”

  28. OKT3 case • WithOKT3, similareffects on animals and humans to those observed with TGN-1412 • In brochure: “Precautions” • “Cytokine release: (…) The anti-CD3 monoclonal antibodyOKT-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.”

  29. 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.

  30. Doses administered and timing Only 10 minutes between administrations

  31. 4. Measures/Recommandations TGN-1412

  32. 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

  33. ESG Recommandations to optimize security : Experts • Assessment of 1st in man trial should be sciences-based 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

  34. 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 • EstimatingFIH starting doses and dose escalation • Understanding and projecting the likely effects of the first pharmacologically active dose administered to humans.

  35. What about today ? - TeGenerowent 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

  36. BIA 10-2474

  37. Actors

  38. 1.The study BIA 10-2474

  39. Molecule : BIA 10-2474 • Inhibitor of fatty acid amide hydrolase (FAAH) • Indication : Neuropathic Pain • (According to Bial, Reversible Inhibitor)

  40. FAAH : Fatty Acid Amid Hydrolase • Serine hydrolase with an unusual Ser-Ser-Lys catalytic triad • After release of Anandamid, cause • its hydrolysis • Anandamid + H20 ← → arachidonic acid + ethanolamin

  41. Anandamid • ⅓ Endocannanabinoid • Inhibition by FAAH → Anandamid degradation inhibition → Anandamid • High affinity for CB1 receptor and low affinity for CB2 • Retrograde action Anandamid

  42. Mechanism of action

  43. Preclinical studies  4 species instead of 2

  44. Preclinical studies

  45. Protocol • Phase I • Single-centre • Double-blind • Randomized • Placebo-controlled • Including additional FI and PD part •  To assess safety andtolerability of BIA 10-2474 after SAD and MAD •  To characterize the PK and PD and assess several potential PD effects.

  46. Dose escalation SAD Cohort MAD Cohort • Once daily D1 to D10 • Dose levels: afterevaluationof safety , tolerability and available PK results of previous of SAD and MAD dose groups • PK and PD assessment • 5 foldincreasefrom the first dose 0,25 mg to the second • 2-fold until100 mg

  47. Inclusion/Exclusion Criteria Inclusion Criteria Exclusion 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 • Subjects withsurgeryhistory, • History of hyperemesis,atopy, alcoholism or drug abuse • Significant infection or known inflammatory process

  48. 2. What happened ? BIA 10-2474

  49. Chronology 1stsubject declared brain dead • 06/01 • 10/01 • 12/01 • 14/01 • 11/01 • 13/01 • 17/01 Authorities notified 1st subject was hospitalized 1stsubject slips into coma Study stopped 50 mg dose Cohort 5 5 subjects were hospitalized 1st subject died

  50. 3. Authorities Investigations BIA 10-2474

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