Introduction to clinical trials

1. Ahmed Zeeneldin
Associate Prof of Medical Oncology

2. ž Clinical :
¡ Humans
¡ Human material
¡ Identifiable data
ž Preclinical:
¡ Animal
¡ Basic
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3. ž Practice:
¡ Standard
¡ approved
¡ benefit
ž Research: may not always benefit:
¡ Non-standard
¡ Non-approved
¡ Benefit?
¢ May receive highest care
¢ May directly benefit
¢ May be harmed
ž Research gives Knowledge for better health
ž Individual: respect, safety and dignity
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4. ž Early on:
¡ Research and practice were merged
ž Later on:
¡ Prior research had set routine care
¢ Clinicians
¡ Unanswered questions or unmet needs
¢ Researchers
¢ New practice
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5. ž Natural sources:
¡ e.g. colics and herbs
ž 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 response
ž Individualization:
¡ Genomes and proteomes
¡ e.g. gene insertion, cancer vaccines
¡ For the single patient with almost 100% success rate
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7. ž 2850 to 525 bc.
ž Imhotep:
¡ surgery,
¡ dentistry,
¡ extracted
medicine from
plants,
¡ position and
function of the
vital organs.,
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11. ž Shen Nung (2737 bc)
¡ experimented with poisons
¡ classified medical plants
ž I. Yin (1176–1123 bc),
¡ extraction of medicines
from boiling plants.
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12. ž father of modern medicine
ž clinical inspection, observation,
and documentation
ž Hippocratic oath and high moral
standards.
ž 42 case records:
¡ malarial fevers,
¡ diarrhea,
¡ dysentery,
¡ mania, and
¡ Pulmonary edema
ž Cleanliness: pure or boiled,
hands and nails
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13. ž Physician of the Roman
Emperor Marcus Aurelius.
ž First to do animal studies
ž Transection of the spinal
cord
ž Described structures:
¡ nervous system,
¡ heart,
¡ kidneys
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14. ‫‪ ž‬ﺗﺪاووا.. ﻓﺈن ﷲ ﺗﻌﺎﻟﻰ ﻟﻢ ﻳﻀﻊ داء إﻻ وﺿﻊ ﻟﻪ دواء..‬
‫ﻏﯿﺮ داء واﺣﺪ: اﻟﮫﺮم(‬
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15. ‫‪ 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 - اﺑﻦ‬
‫ﺳﻌﺪ - اﺑﻦ ﻣﺎﺳﻮﻳﻪ - أﺑﻮ اﻟﻨﺼﺮ اﻟﺘﻜﺮﻳﺘﻲ - اﺑﻦ ﺗﻮﻣﺎ - اﺑﻦ‬
‫ﺳﻘﻼب - اﺑﻦ اﻟﻤﺠﻮﺳﻲ - اﻹدرﻳﺴﻲ - اﺑﻦ اﻟﺠﺰار -‬
‫اﺑﻦ ﺳﻤﺠﻮن - اﺑﻦ اﻟﻤﻘﺸﺮ - اﻟﺒﻐﺪادي - اﺑﻦ ﺟﺰﻟﺔ - اﺑﻦ‬
‫اﻟﺴﻤﺢ - 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-‬
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16. ‫‪ ž‬اﺑﻦ اﻟﻨﻔﯿﺲ:‬
‫¡ ﻗﺪم وﺻﻔًﺎ دﻗﯿﻘًﺎ ﻟﻠﺪورة‬
‫اﻟﺪﻣﻮﻳﺔ اﻟﺼﱡﻐْﺮَى ، ﻟﻢ‬
‫ﻳُﺴﺒَﻖْ إﻟﯿﻪ.‬
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17. ‫‪ 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.‬
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18. ‫‪ 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(‬
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19. ‫‪ 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( ‪ALTASRIF‬‬
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20. ‫‪ 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 ‫¡‬
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23. 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 PF
ž Hand scrubbing with chlorinated lime water
before entering the maternity ward
ž Mortality dropped from 9.92 % to 1.27%
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24. ž On concentration camp inmates.
ž Auschwitz, Poland
ž mass sterilization of females by injecting
caustics into uterus
ž Men had mass irradiation
followed by castration so that
the testes could be examined.
ž People were killed to collect
skeleton gallery
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25. ž Sigmund Rascher
ž Pilots shot down in North Sea
ž 300 prisoners
ž immersed in ice-cold water, or
ž Strapped naked to a stretcher
in the Polish winter
¡ meticulously monitored for
rectal temperature,
heart rate, shivering
level of consciousness
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26. ž Most were allowed to freeze to death;
ž some resuscitation by various methods
ž Active reheating in a warm bath proving the
most effective.
ž results were presented at a medical
conference in Berlin in 1942.
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27. ž Eppinger,
ž Forced 90 prisoners to drink only seawater
for up to 12 days
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28. ž Germany
ž 1947
ž war crimes tribunal
ž Many Nazi doctors were
found guilty
ž Some jailed, some excuted
and some suicided
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29. 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.
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30. ž 2. Research Aim
¡ Fruitful and good of society,
¡ unprocurable by other methods or means of
study,
¡ not random and unnecessary in nature.
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31. ž 3. Trial to be based on prior knowledge
¡ Animal studies
¡ Natural history
¡ Expected outcome to justify the trial
ž 4. avoid sufferings
ž 5. Not when priori reason to believe that
death or disabling injury will occur
ž 6. Risk should not exceed expected benefit
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32. ž 7. precautions to protect patients from
injury, disability or death
ž 8. Qualified persons
ž 9. Right to withdraw
ž 10. trial termination when experiment is
likely to result in injury, disability, or death
to the experimental subject
Ahmed Zeeneldin 32

33. ž World Medical Association
ž 1964 (18th general assembly )
ž Helsinki, Finland
ž Amendments:
¡ 1975, Japan
¡ 1983, Italy
¡ 1989, Hong Kong
¡ 1996, South Africa
¡ 2000, Scotland
¡ 2002, Washington
¡ 2004, Japan
Ahmed Zeeneldin 33

34. ž Ethical rules
¡ Humans
¡ Human material
¡ identifiable data
ž Physician duty is to promote and safeguard
the health of the people
ž A physician shall act only in the patient's
interest
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35. ž medical progress needs research
ž 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
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36. 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
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37. 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 knowledge
ž Environment and animals
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38. 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

39. ž Risk/benefit assessment
ž 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 project
ž Subject:
¡ Respect,
¡ Privacy and confidentiality
ž
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40. 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
¡ WITHDRAWAL
ž Who gets the consent:
¡ No dureness
¡ Dependency: treating doctor!
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41. ž Legally
incompetent, physically or mentally
incapable:
¡ legally authorized representative
¡ Better avoid if possible
ž Assentof child plus consent of legally
authorized representative
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42. ž Bothauthors and publishers have ethical
obligations.
¡ Accuracy
¡ Negative as well as positive
¡ conflicts of interest
¡ Declaration compliance
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43. 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.
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44. ž Placebo-controlled trials
¡ Active copamparators
ž Post therapy access to medications
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45. 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.
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46. ž Clinical trials consist of four phases
ž the first three occur before a license is
granted and
ž the last is conducted as a post-licensing
phase.
ž Each phase varies in size, character and
focus:
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47. ž LAB
ž ROOT OF CLINICAL RESEARCH
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48. ž Animal studies
ž Safety and efficacy
ž How to assess first in human dose:
¡ NOAEL
¡ Human equivalent dose
¡ Safety factor
¡ PREDICTABILITY
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49. ž primarily determines:
¡ how a medicine works in humans and
¡ helps to predict the dosage range for the
medicine, and
ž involves
healthy volunteers (cancer
chemotherapy is an exception).
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50. 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.
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51. ž involves a much larger group (1000-5000) of
these patients which
ž Will help determine if the medicine can be
considered both safe and effective.
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52. ž TRIALS AFTER A LICENCE
ž 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 which
ž allows results to be developed using a much
larger group of participants.
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53. 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”.
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54. 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?
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55. ž Practice:benefit
ž Research: may not always benefit
¡ May receive highest care
¡ May directly benefit
¡ May be harmed
ž Research gives Knowledge for better health
ž Individual: respect, safety and dignity
Ahmed Zeeneldin 55

56. 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.
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57. ž Individualsare asked to take risk of harm or
burden To benefit others and society
ž Exploitation?
¡ Respect
¡ Contribute not used
¡ Rights and welfare protected
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58. ž Idea
ž Question:
¡ Population
¡ Intervention, comparator
¡ Outcome
ž Literature search
¡ Answered or not answered
¡ Reinventing the wheel?
ž Protocol
ž Scientific and ethical review
ž Conduct
ž Publication
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