Clinical trials 2
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Introduction to clinical trials

Introduction to clinical trials

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  • 1. Ahmed ZeeneldinAssociate Prof of Medical Oncology
  • 2. ž Clinical : ¡ Humans ¡ Human material ¡ Identifiable dataž Preclinical: ¡ Animal ¡ Basic Ahmed Zeeneldin 2
  • 3. ž Practice: ¡ Standard ¡ approved ¡ benefitž Research: may not always benefit: ¡ Non-standard ¡ Non-approved ¡ Benefit? ¢ May receive highest care ¢ May directly benefit ¢ May be harmedž Research gives Knowledge for better healthž Individual: respect, safety and dignity Ahmed Zeeneldin 3
  • 4. ž Early on: ¡ Research and practice were mergedž Later on: ¡ Prior research had set routine care ¢ Clinicians ¡ Unanswered questions or unmet needs ¢ Researchers ¢ New practice Ahmed Zeeneldin 4
  • 5. ž Natural sources: ¡ e.g. colics and herbsž Manufactures : ¡ Isolation ¡ Purification ¡ Medicinalization ¡ All patients: may respond or not (50/50)ž Targeting a disease process: ¡ e.g. hyperacidity and H2 receptos ¡ STI and TKI ¡ in a group of patients more likely to give a responsež Individualization: ¡ Genomes and proteomes ¡ e.g. gene insertion, cancer vaccines ¡ For the single patient with almost 100% success rate Ahmed Zeeneldin 5
  • 6. ž 2850 to 525 bc.ž Imhotep: ¡ surgery, ¡ dentistry, ¡ extracted medicine from plants, ¡ position and function of the vital organs., Ahmed Zeeneldin 7
  • 7. Ahmed Zeeneldin 8
  • 8. Ahmed Zeeneldin 9
  • 9. Ahmed Zeeneldin 10
  • 10. ž Shen Nung (2737 bc) ¡ experimented with poisons ¡ classified medical plantsž I. Yin (1176–1123 bc), ¡ extraction of medicines from boiling plants. Ahmed Zeeneldin 11
  • 11. ž father of modern medicinež clinical inspection, observation, and documentationž Hippocratic oath and high moral standards.ž 42 case records: ¡ malarial fevers, ¡ diarrhea, ¡ dysentery, ¡ mania, and ¡ Pulmonary edemaž Cleanliness: pure or boiled, hands and nails Ahmed Zeeneldin 12
  • 12. ž Physician of the Roman Emperor Marcus Aurelius.ž First to do animal studiesž Transection of the spinal cordž Described structures: ¡ nervous system, ¡ heart, ¡ kidneys Ahmed Zeeneldin 13
  • 13. ‫‪ ž‬ﺗﺪاووا.. ﻓﺈن ﷲ ﺗﻌﺎﻟﻰ ﻟﻢ ﻳﻀﻊ داء إﻻ وﺿﻊ ﻟﻪ دواء..‬ ‫ﻏﯿﺮ داء واﺣﺪ: اﻟﮫﺮم(‬ ‫‪Ahmed Zeeneldin‬‬ ‫41‬
  • 14. ‫‪ ž‬اﺑﻦ أﺑﻲ أﺻﯿﺒﻌﺔ - اﺑﻦ رﺑﱠﻦ اﻟﻄﺒﺮي - اﺑﻦ اﻟﺼﻮري - أﺑﻮ‬ ‫اﻟﺤﻜﻢ اﻟﺪﻣﺸﻘﻲ - اﺑﻦ ﺑﺎﺟﻪ - اﺑﻦ اﻟﺮﺣﺒﻲ - اﺑﻦ اﻟﻌﻄﺎر‬ ‫-أﺑﻮ ﻋﺜﻤﺎن اﻟﺪﻣﺸﻘﻲ - اﺑﻦ اﻟﺒﻄﺮﻳﻖ - اﺑﻦ رﺷﺪ - اﺑﻦ‬ ‫اﻟﻘﺲ - أﺑﻮ اﻟﻔﺮج اﻟﯿﺒﺮودي - اﺑﻦ ﺑﻄﻼن - اﺑﻦ اﻟﻘﻒ - أﺑﻮ‬ ‫اﻟﻔﻀﻞ اﻟﺤﺎرﺛﻲ - اﺑﻦ اﻟﺒﯿﻄﺎر - اﺑﻦ اﻟﺴﺮاج - اﺑﻦ‬ ‫ﻛﺸﻜﺎرﻳﺎ - أﺑﻮ اﻟﻘﺎﺳﻢ اﻟﺰھﺮاوي - اﺑﻦ اﻟﺘﻠﻤﯿﺬ - اﺑﻦ‬‫ﺳﻌﺪ - اﺑﻦ ﻣﺎﺳﻮﻳﻪ - أﺑﻮ اﻟﻨﺼﺮ اﻟﺘﻜﺮﻳﺘﻲ - اﺑﻦ ﺗﻮﻣﺎ - اﺑﻦ‬ ‫ﺳﻘﻼب - اﺑﻦ اﻟﻤﺠﻮﺳﻲ - اﻹدرﻳﺴﻲ - اﺑﻦ اﻟﺠﺰار -‬‫اﺑﻦ ﺳﻤﺠﻮن - اﺑﻦ اﻟﻤﻘﺸﺮ - اﻟﺒﻐﺪادي - اﺑﻦ ﺟﺰﻟﺔ - اﺑﻦ‬‫اﻟﺴﻤﺢ - اﺑﻦ ﻣﻠﻜﺎ - اﻟﺒﯿﺮوﻧﻲ - اﺑﻦ ﺟﻠﺠﻞ - اﺑﻦ ﺳﯿﻨﺎ‬‫-اﺑﻦ ﻣﻨﺪوﻳﻪ - ﺛﺎﺑﺖ ﺑﻦ ﻗﺮة - اﺑﻦ اﻟﺨﻄﯿﺐ - اﺑﻦ اﻟﺼﺒﺎغ -‬ ‫اﺑﻦ ﻣﮫﻨﺪ - اﻟﺮازي - اﺑﻦ اﻟﺨﻮام - اﺑﻦ ﺻﻐﯿﺮ - اﺑﻦ‬ ‫اﻟﻨﻔﯿﺲ - اﺑﻦ اﻟﺨﯿﺎط - اﺑﻦ اﻟﺼﻼح - اﺑﻦ اﻟﮫﯿﺜﻢ -‬ ‫ﻣﻮﻓﻖ اﻟﺪﻳﻦ ﻋﺒﺪ اﻟﻠﻄﯿﻒ اﻟﺒﻐﺪادي - ﻋﺰ اﻟﺪﻳﻦ ﺑﻦ‬ ‫اﻟﺴﻮﻳﺪي - رﺷﯿﺪ اﻟﺪﻳﻦ ﻋﻠﻲ ﺑﻦ ﺧﻠﯿﻔﺔ - ﻋﻠﻲ ﺑﻦ‬ ‫رﺿﻮان - اﺑﻦ زھﺮ-‬ ‫‪Ahmed Zeeneldin‬‬ ‫51‬
  • 15. ‫‪ ž‬اﺑﻦ اﻟﻨﻔﯿﺲ:‬ ‫¡ ﻗﺪم وﺻﻔًﺎ دﻗﯿﻘًﺎ ﻟﻠﺪورة‬ ‫اﻟﺪﻣﻮﻳﺔ اﻟﺼﱡﻐْﺮَى ، ﻟﻢ‬ ‫ﻳُﺴﺒَﻖْ إﻟﯿﻪ.‬‫‪Ahmed Zeeneldin‬‬ ‫61‬
  • 16. ‫‪ ž‬أﺑﻮ ﺑﻜﺮاﻟﺮازي :‬ ‫‪ ž‬واﺑﺘﻜﺮ ﺧﯿﻮط اﻟﺠﺮاﺣﺔ اﻟﻤﻌﺮوﻓﺔ ﺑﺎﻟﻘﺼﺎب،‬ ‫‪ ž‬أول ﻣﻦ ﺻﻨﻊ ﻣﺮاھﻢ اﻟﺰﺋﺒﻖ،‬ ‫‪ ž‬وﻗﺪم ﺷﺮﺣﺎ ﻣﻔﺼﻼ ً ﻷﻣﺮاض اﻷطﻔﺎل، واﻟﻨﺴﺎء‬ ‫واﻟﻮﻻدة، واﻷﻣﺮاض اﻟﺘﻨﺎﺳﻠﯿﺔ، وﺟﺮاﺣﺔ اﻟﻌﯿﻮن‬ ‫وأﻣﺮاﺿﮫﺎ..‬‫‪ ž‬وﻛﺎن ﻣﻦ رواد اﻟﺒﺤﺚ اﻟﺘﺠﺮﻳﺒﻲ ﻓﻲ اﻟﻌﻠﻮم اﻟﻄﺒﯿﺔ،‬ ‫وﻗﺪ ﻗﺎم ﺑﻨﻔﺴﻪ ﺑﺒﻌﺾ اﻟﺘﺠﺎرب ﻋﻠﻰ اﻟﺤﯿﻮاﻧﺎت‬ ‫ﻛﺎﻟﻘﺮود؛ ﻓﻜﺎن ﻳﻌﻄﯿﮫﺎ اﻟﺪواء، وﻳﻼﺣﻆ ﺗﺄﺛﯿﺮه ﻓﯿﮫﺎ،‬ ‫ﻓﺈذا ﻧﺠﺢ طﺒﻘﻪ ﻋﻠﻰ اﻹﻧﺴﺎن..‬‫‪ ž‬وﻳُﻌَﺪﱡ اﻟﺮﱠازِي أول ﻣﻦ ﻗﺮر أن اﻟﻤﺮض ﻗﺪ ﻳﻜﻮن وراﺛﯿًﺎ.‬ ‫‪Ahmed Zeeneldin‬‬ ‫71‬
  • 17. ‫‪ ž‬أﺑﻮ ﺑﻜﺮاﻟﺮازي :‬ ‫‪ ž‬وﻧﺼﺢ ﺑﺄن ﺗُﺒﻨﻰ‬ ‫اﻟﻤﺴﺘﺸﻔﯿﺎت ﺑﻌﯿﺪًا ﻋﻦ‬ ‫أﻣﺎﻛﻦ ﺗﻌﻔﱡﻦ اﻟﻤﻮاد‬ ‫اﻟﻌﻀﻮﻳﺔ‬ ‫‪ ž‬وﻳُﻌﺘَﺒَﺮُ اﻟﺮازي ﺳﺒﺎﻗًﺎ ﻓﻲ‬ ‫ﺗﺸﺨﯿﺼﻪ ﻟﻠﺠﺪري‬ ‫واﻟﺤﺼﺒﺔ، وﻗﺪ وﺿﻊ ﻟﺬﻟﻚ‬ ‫ﻛﺘﺎﺑﻪ اﻟﺸﮫﯿﺮ )اﻟﺠﺪري‬ ‫واﻟﺤﺼﺒﺔ(‬‫‪Ahmed Zeeneldin‬‬ ‫81‬
  • 18. ‫‪ ž‬أﺑﻲ اﻟﻘﺎﺳﻢ اﻟﺰھﺮاوي :‬ ‫اﺧﺘﺮاع أوﻟﻰ أدوات اﻟﺠﺮاﺣﺔ‬ ‫¡‬ ‫ﻛﺎﻟﻤﺸﺮط واﻟﻤﻘﺺ‬ ‫اﻟﺠﺮاﺣﻲ‬ ‫رﺑﻂ اﻷوﻋﯿﺔ ﻟﻤﻨﻊ ﻧﺰﻓﮫﺎ‬ ‫¡‬ ‫اﻟﻮاﺿﻊ اﻷول ﻟﻌﻠﻢ اﻟﻤﻨﺎظﯿﺮ‬ ‫¡‬ ‫اﻟﺠﺮاﺣﯿﺔ‬ ‫أول ﻣﺨﺘﺮع وﻣﺴﺘﺨﺪم‬ ‫¡‬ ‫ﻟﻤﻨﻈﺎر اﻟﻤﮫﺒﻞ‬ ‫ﻛﺘﺎب : )اﻟﺘﺼﺮﻳﻒ ﻟﻤﻦ ﻋﺠﺰ‬ ‫¡‬ ‫ﻋﻦ اﻟﺘﺄﻟﯿﻒ( ‪ALTASRIF‬‬‫‪Ahmed Zeeneldin‬‬ ‫91‬
  • 19. ‫‪ ž‬اﺑﻦ ﺳﯿﻨﺎ :‬ ‫اﻛﺘﺸﻒ ﻷول ﻣﺮة طﻔﯿﻞ‬ ‫¡‬ ‫)اﻹﻧﻜﻠﺴﺘﻮﻣﺎ(، وﺳﻤﺎھﺎ اﻟﺪودة‬ ‫اﻟﻤﺴﺘﺪﻳﺮة‬ ‫أول ﻣﻦ وﺻﻒ اﻻﻟﺘﮫﺎب‬ ‫¡‬ ‫اﻟﺴﺤﺎﺋﻲ‬ ‫طﺮﻳﻘﺔ اﺳﺘﺌﺼﺎل )اﻟﻠﻮزﺗﯿﻦ(،‬ ‫¡‬ ‫وﺗﻨﺎول ﻓﻲ آراﺋﻪ اﻟﻄﺒﯿﺔ أﻧﻮاﻋًﺎ‬ ‫¡‬ ‫ﻣﻦ اﻟﺴﺮطﺎﻧﺎت ﻛﺴﺮطﺎن‬ ‫اﻟﻜﺒﺪ، واﻟﺜﺪي، وأورام اﻟﻌﻘﺪ‬ ‫اﻟﻠﯿﻤﻔﺎوﻳﺔ‬ ‫ﻗﺎم ﺑﻌﻤﻠﯿﺎت ﺟﺮاﺣﯿﺔ دﻗﯿﻘﺔ‬ ‫¡‬‫‪Ahmed Zeeneldin‬‬ ‫02‬
  • 20. Ahmed Zeeneldin 21
  • 21. Ahmed Zeeneldin 22
  • 22. ž IgnazPhilipp Semmelweis (1818–1865)ž Death rate from puerperal fever (PF) was ¡ high in wards run by physicians (10%) ¡ low in wards run by midwives (2-3%).ž Following death of a fellow after having a small cut wound during autopsy of a woman died of PFž Hand scrubbing with chlorinated lime water before entering the maternity wardž Mortality dropped from 9.92 % to 1.27% Ahmed Zeeneldin 23
  • 23. ž On concentration camp inmates.ž Auschwitz, Polandž mass sterilization of females by injecting caustics into uterusž Men had mass irradiation followed by castration so that the testes could be examined.ž People were killed to collect skeleton gallery Ahmed Zeeneldin 24
  • 24. ž Sigmund Rascherž Pilots shot down in North Seaž 300 prisonersž immersed in ice-cold water, orž Strapped naked to a stretcher in the Polish winter ¡ meticulously monitored for rectal temperature, heart rate, shivering level of consciousness Ahmed Zeeneldin 25
  • 25. ž Most were allowed to freeze to death;ž some resuscitation by various methodsž Active reheating in a warm bath proving the most effective.ž results were presented at a medical conference in Berlin in 1942. Ahmed Zeeneldin 26
  • 26. ž Eppinger,ž Forced 90 prisoners to drink only seawater for up to 12 days Ahmed Zeeneldin 27
  • 27. ž Germanyž 1947ž war crimes tribunalž Many Nazi doctors were found guiltyž Some jailed, some excuted and some suicided Ahmed Zeeneldin 28
  • 28. ž 1. The voluntary consent of the human subject is absolutely essential. ¡ Capacity ¡ Free power of choice, ¡ No constraint or coercion, ¡ Sufficient knowledge and comprehension. Ahmed Zeeneldin 29
  • 29. ž 2. Research Aim ¡ Fruitful and good of society, ¡ unprocurable by other methods or means of study, ¡ not random and unnecessary in nature. Ahmed Zeeneldin 30
  • 30. ž 3. Trial to be based on prior knowledge ¡ Animal studies ¡ Natural history ¡ Expected outcome to justify the trialž 4. avoid sufferingsž 5. Not when priori reason to believe that death or disabling injury will occurž 6. Risk should not exceed expected benefit Ahmed Zeeneldin 31
  • 31. ž 7. precautions to protect patients from injury, disability or deathž 8. Qualified personsž 9. Right to withdrawž 10. trial termination when experiment is likely to result in injury, disability, or death to the experimental subject Ahmed Zeeneldin 32
  • 32. ž World Medical Associationž 1964 (18th general assembly )ž Helsinki, Finlandž Amendments: ¡ 1975, Japan ¡ 1983, Italy ¡ 1989, Hong Kong ¡ 1996, South Africa ¡ 2000, Scotland ¡ 2002, Washington ¡ 2004, Japan Ahmed Zeeneldin 33
  • 33. ž Ethical rules ¡ Humans ¡ Human material ¡ identifiable dataž Physician duty is to promote and safeguard the health of the peoplež A physician shall act only in the patients interest Ahmed Zeeneldin 34
  • 34. ž medical progress needs researchž Subjects are more important than interests of science and society.ž Aim: ¡ improve prophylactic, diagnostic and therapeutic procedures and ¡ the understanding of the aetiology and pathogenesis of disease.ž 7. Most research involve risks and burdens Ahmed Zeeneldin 35
  • 35. ž Respectfor all human beings and protect their health and rights. ¡ Vulnerable need special protection.ž Researchers should be aware of the ethical, legal and regulatory requirements Ahmed Zeeneldin 36
  • 36. ž Itis the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.ž Research should be based on accepted scientific principles and thorough knowledgež Environment and animals Ahmed Zeeneldin 37
  • 37. ž Protocol is a must ¡ Review by independent body ¡ Ethical review committee (EC/ERC/IRB)ž The research protocol should always contain: ¡ a statement of the ethical considerations involved and ¡ indicate that there is compliance with the principles of this Declaration.ž Qualified person ¡ Responsible for safety ¡ Not the subject even consenting Ahmed Zeeneldin 38
  • 38. ž Risk/benefit assessmentž populations in which the research is carried out stand to benefit from the results of the research.ž The subjects must be volunteers and informed participants in the research projectž Subject: ¡ Respect, ¡ Privacy and confidentialityž Ahmed Zeeneldin 39
  • 39. ž Informed consent: ¡ aims, methods, ¡ sources of funding, any possible conflicts of interest, institutional affiliations of the ¡ researcher, ¡ the anticipated benefits and potential risks of the study and the discomfort ¡ SIGN AND DATE ¡ Unable to sign: witnessed ¡ Copy to patient and another in the file ¡ WITHDRAWALž Who gets the consent: ¡ No dureness ¡ Dependency: treating doctor! Ahmed Zeeneldin 40
  • 40. ž Legally incompetent, physically or mentally incapable: ¡ legally authorized representative ¡ Better avoid if possiblež Assentof child plus consent of legally authorized representative Ahmed Zeeneldin 41
  • 41. ž Bothauthors and publishers have ethical obligations. ¡ Accuracy ¡ Negative as well as positive ¡ conflicts of interest ¡ Declaration compliance Ahmed Zeeneldin 42
  • 42. ž At the conclusion of the study: ¡ access to the best proven methods identified by the study.ž refusalof a patient to participate in a study must never interfere with the patient- physician relationship. Ahmed Zeeneldin 43
  • 43. ž Placebo-controlled trials ¡ Active copamparatorsž Post therapy access to medications Ahmed Zeeneldin 44
  • 44. ž At the conclusion of the study: ¡ access to the best proven methods identified by the study.ž refusalof a patient to participate in a study must never interfere with the patient- physician relationship. Ahmed Zeeneldin 45
  • 45. ž Clinical trials consist of four phasesž the first three occur before a license is granted andž the last is conducted as a post-licensing phase.ž Each phase varies in size, character and focus: Ahmed Zeeneldin 46
  • 46. ž LABž ROOT OF CLINICAL RESEARCH Ahmed Zeeneldin 47
  • 47. ž Animal studiesž Safety and efficacyž How to assess first in human dose: ¡ NOAEL ¡ Human equivalent dose ¡ Safety factor ¡ PREDICTABILITY Ahmed Zeeneldin 48
  • 48. ž primarily determines: ¡ how a medicine works in humans and ¡ helps to predict the dosage range for the medicine, andž involves healthy volunteers (cancer chemotherapy is an exception). Ahmed Zeeneldin 49
  • 49. ž testsefficacy as well as safety among:ž a small group of patients (100-300)ž with the condition for which the medicine has been developed. Ahmed Zeeneldin 50
  • 50. ž involves a much larger group (1000-5000) of these patients whichž Will help determine if the medicine can be considered both safe and effective. Ahmed Zeeneldin 51
  • 51. ž TRIALS AFTER A LICENCEž Phase 4 trials are conducted after a medicine has been granted a license.ž In these studies a medicine is prescribed in an everyday healthcare environment whichž allows results to be developed using a much larger group of participants. Ahmed Zeeneldin 52
  • 52. ž Phase 4 trials are performed to: ¡ Develop new treatment uses for the medicine. ¡ Compare with other treatments for the condition. ¡ Determine the clinical effectiveness of the medicine in a much wider variety of patient types in conditions of “real life”. Ahmed Zeeneldin 53
  • 53. ž Could fruits cure scurvy in sailors with scurvy when compared with other forms?ž Could hand washing prevent PF in women after delivery as compared with no hand washing? Ahmed Zeeneldin 54
  • 54. ž Practice:benefitž Research: may not always benefit ¡ May receive highest care ¡ May directly benefit ¡ May be harmedž Research gives Knowledge for better healthž Individual: respect, safety and dignity Ahmed Zeeneldin 55
  • 55. ž Because human beings should never be used “merely as means to an end, but always as ends in themselves,” the need to respect and protect human participants in research is paramount. Ahmed Zeeneldin 56
  • 56. ž Individualsare asked to take risk of harm or burden To benefit others and societyž Exploitation? ¡ Respect ¡ Contribute not used ¡ Rights and welfare protected Ahmed Zeeneldin 57
  • 57. ž Ideaž Question: ¡ Population ¡ Intervention, comparator ¡ Outcomež Literature search ¡ Answered or not answered ¡ Reinventing the wheel?ž Protocolž Scientific and ethical reviewž Conductž Publication Ahmed Zeeneldin 58
  • 58. Ahmed Zeeneldin 59