Clinical trials 2

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Ahmed Zeeneldin Associate Prof of Medical Oncology

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Introduction to clinical trials

Transcript of Clinical trials 2

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Ahmed ZeeneldinAssociate Prof of Medical Oncology

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û Clinical :¡ Humans¡ Human material¡ Identifiable data

û Preclinical: ¡ Animal ¡ Basic

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û Practice: ¡ Standard¡ approved¡ benefit

û Research: may not always benefit:¡ Non-standard¡ Non-approved¡ Benefit?¢ May receive highest care¢ May directly benefit¢ May be harmed

û Research gives Knowledge for better healthû Individual: respect, safety and dignity

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û Early on: ¡ Research and practice were merged

û Later on:¡ Prior research had set routine care¢ Clinicians

¡ Unanswered questions or unmet needs¢ Researchers ¢ New practice

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û Natural sources:¡ e.g. colics and herbs

û Manufactures :¡ Isolation¡ Purification¡ Medicinalization¡ All patients: may respond or not (50/50)

û Targeting a disease process:¡ e.g. hyperacidity and H2 receptos¡ STI and TKI¡ in a group of patients more likely to give a response

û Individualization:¡ Genomes and proteomes¡ e.g. gene insertion, cancer vaccines ¡ For the single patient with almost 100% success rate

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û 2850 to 525 bc.û Imhotep: ¡ surgery, ¡ dentistry,¡ extracted

medicine from plants, ¡ position and

function of the vital organs.,

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û Shen Nung (2737 bc)¡ experimented with poisons¡ classified medical plants

û I. Yin (1176–1123 bc),¡ extraction of medicines

from boiling plants.

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û father of modern medicine û clinical inspection, observation,

and documentationû Hippocratic oath and high moral

standards.û 42 case records:¡ malarial fevers, ¡ diarrhea,¡ dysentery,¡ mania, and ¡ Pulmonary edema

û Cleanliness: pure or boiled, hands and nails

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û Physician of the Roman Emperor Marcus Aurelius.

û First to do animal studiesû Transection of the spinal

cordûDescribed structures:¡ nervous system,¡ heart, ¡ kidneys

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ûفإن هللا تعالى لم يضع داء إال وضع له دواء.. تداووا ..)الھرم: غیر داء واحد

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ûأبو -ابن الصوري-ابن ربن الطبري-ابن أبي أصیبعةابن العطار-ابن الرحبي-ابن باجه-الحكم الدمشقي

ابن -ابن رشد-ابن البطريق-أبو عثمان الدمشقي-أبو -ابن القف-ابن بطالن-أبو الفرج الیبرودي-القس

ابن -ابن السراج-ابن البیطار-الفضل الحارثيابن -ابن التلمیذ-أبو القاسم الزھراوي-كشكاريا

ابن -ابن توما-أبو النصر التكريتي-ابن ماسويه-سعد-ابن الجزار-اإلدريسي-ابن المجوسي-سقالب

ابن -ابن جزلة-البغدادي-ابن المقشر-ابن سمجونابن سینا-ابن جلجل-البیروني-ابن ملكا-السمح

-ابن الصباغ-ابن الخطیب-ثابت بن قرة-ابن مندويه-ابن -ابن صغیر-ابن الخوام-الرازي-ابن مھند-ابن الھیثم-ابن الصالح-ابن الخیاط-النفیس

عز الدين بن -موفق الدين عبد اللطیف البغداديعلي بن -رشید الدين علي بن خلیفة-السويدي

-ابن زھر-رضوان

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ûابن النفیس:قدم وصفا دقیقا للدورة ¡

الدموية الصغرى ، لم سبق إلیه .ي

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û أبو بكرالرازي:û ،وابتكر خیوط الجراحة المعروفة بالقصابû ،أول من صنع مراھم الزئبقûوالنساء ، وقدم شرحا مفصال ألمراض األطفال

وجراحة العیون ، واألمراض التناسلیة، والوالدة.. وأمراضھا

û ،وكان من رواد البحث التجريبي في العلوم الطبیةوقد قام بنفسه ببعض التجارب على الحیوانات

كالقرود؛ فكان يعطیھا الدواء، ويالحظ تأثیره فیھا، .. فإذا نجح طبقه على اإلنسان

ûويعد الرازي أول من قرر أن المرض قد يكون وراثیا.Ahmed Zeeneldin 17

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û أبو بكرالرازي:û بنى ونصح بأن ت

المستشفیات بعیدا عن ن المواد أماكن تعف

العضويةû ويعتبر الرازي سباقا في

تشخیصه للجدري والحصبة، وقد وضع لذلك

الجدري (كتابه الشھیر )والحصبة

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û أبي القاسم الزھراوي:اختراع أولى أدوات الجراحة ¡

كالمشرط والمقص الجراحي

ربط األوعیة لمنع نزفھا¡الواضع األول لعلم المناظیر ¡

الجراحیةأول مخترع ومستخدم ¡

لمنظار المھبلالتصريف لمن عجز : (كتاب ¡

ALTASRIF) عن التألیف

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û ابن سینا:اكتشف ألول مرة طفیل ¡

وسماھا الدودة ، )اإلنكلستوما(المستديرة

أول من وصف االلتھاب ¡السحائي

، )اللوزتین(طريقة استئصال ¡وتناول في آرائه الطبیة أنواعا ¡

من السرطانات كسرطان الكبد، والثدي، وأورام العقد

اللیمفاويةقام بعملیات جراحیة دقیقة¡

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û Ignaz Philipp Semmelweis (1818–1865)ûDeath rate from puerperal fever (PF) was¡ high in wards run by physicians (10%)¡ low in wards run by midwives (2-3%).

û Following death of a fellow after having a small cut wound during autopsy of a woman died of PF

ûHand scrubbing with chlorinated lime water before entering the maternity ward

ûMortality dropped from 9.92 % to 1.27%

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ûOn concentration camp inmates.û Auschwitz, Polandûmass sterilization of females by injecting

caustics into uterusûMen had mass irradiation

followed by castration so that the testes could be examined.

û People were killed to collectskeleton gallery

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û Sigmund Rascherû Pilots shot down in North Seaû 300 prisonersû immersed in ice-cold water, or û Strapped naked to a stretcher

in the Polish winter¡ meticulously monitored for

rectal temperature, heart rate, shivering level of consciousness

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ûMost were allowed to freeze to death;û some resuscitation by various methodsû Active reheating in a warm bath proving the

most effective.û results were presented at a medical

conference in Berlin in 1942.

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û Eppinger,û Forced 90 prisoners to drink only seawater

for up to 12 days

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ûGermanyû 1947ûwar crimes tribunalûMany Nazi doctors were

found guiltyû Some jailed, some excuted

and some suicided

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û 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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û 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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û 3. Trial to be based on prior knowledge ¡ Animal studies¡ Natural history¡ Expected outcome to justify the trial

û 4. avoid sufferingsû 5. Not when priori reason to believe that

death or disabling injury will occurû 6. Risk should not exceed expected benefit

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û 7. precautions to protect patients from injury, disability or death

û 8. Qualified personsû 9. Right to withdrawû 10. trial termination when experiment is

likely to result in injury, disability, or death to the experimental subject

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ûWorld Medical Associationû 1964 (18th general assembly )ûHelsinki, Finlandû Amendments:¡ 1975, Japan¡ 1983, Italy¡ 1989, Hong Kong¡ 1996, South Africa¡ 2000, Scotland¡ 2002, Washington¡ 2004, Japan

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û Ethical rules¡ Humans¡ Human material¡ identifiable data

û Physician duty is to promote and safeguard the health of the people

û A physician shall act only in the patient's interest

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ûmedical progress needs researchû Subjects are more important than interests

of science and society.û Aim: ¡ improve prophylactic, diagnostic and therapeutic

procedures and ¡ the understanding of the aetiology and

pathogenesis of disease.

û 7. Most research involve risks and burdens

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û Respect for all human beings and protect their health and rights.¡ Vulnerable need special protection.

û Researchers should be aware of the ethical, legal and regulatory requirements

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û It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.

û Research should be based on accepted scientific principles and thorough knowledge

û Environment and animals

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û Protocol is a must¡ Review by independent body¡ Ethical review committee (EC/ERC/IRB)

û 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.

ûQualified person¡ Responsible for safety¡ Not the subject even consenting

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û Risk/benefit assessmentû populations in which the research is carried

out stand to benefit from the results of the research.

û The subjects must be volunteers and informed participants in the research project

û Subject:¡ Respect,¡ Privacy and confidentiality


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û 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

ûWho gets the consent:¡ No dureness¡ Dependency: treating doctor!

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û Legally incompetent, physically or mentally incapable:¡ legally authorized representative¡ Better avoid if possible

û Assent of child plus consent of legally authorized representative

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û Both authors and publishers have ethical obligations.¡ Accuracy¡ Negative as well as positive¡ conflicts of interest¡ Declaration compliance

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û At the conclusion of the study:¡ access to the best proven methods identified by

the study.

û refusal of a patient to participate in a study must never interfere with the patient-physician relationship.

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û Placebo-controlled trials¡ Active copamparators

û Post therapy access to medications

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û At the conclusion of the study:¡ access to the best proven methods identified by

the study.

û refusal of a patient to participate in a study must never interfere with the patient-physician relationship.

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û Clinical trials consist of four phasesû the first three occur before a license is

granted andû the last is conducted as a post-licensing

phase. û Each phase varies in size, character and


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û Animal studies û Safety and efficacyûHow to assess first in human dose: ¡ NOAEL¡ Human equivalent dose¡ Safety factor¡ PREDICTABILITY

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û primarily determines:¡ how a medicine works in humans and ¡ helps to predict the dosage range for the

medicine, and

û involves healthy volunteers (cancer chemotherapy is an exception).

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û tests efficacy as well as safety among:û a small group of patients (100-300) ûwith the condition for which the medicine

has been developed.

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û involves a much larger group (1000-5000) of these patients which

ûWill help determine if the medicine can be considered both safe and effective.

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û TRIALS AFTER A LICENCEû Phase 4 trials are conducted after a medicine

has been granted a license. û In these studies a medicine is prescribed in

an everyday healthcare environment which û allows results to be developed using a much

larger group of participants.

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û 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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û Could fruits cure scurvy in sailors with scurvy when compared with other forms?

û Could hand washing prevent PF in women after delivery as compared with no hand washing?

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û Practice: benefitû Research: may not always benefit¡ May receive highest care¡ May directly benefit¡ May be harmed

û Research gives Knowledge for better healthû Individual: respect, safety and dignity

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û 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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û Individuals are asked to take risk of harm or burden To benefit others and society

û Exploitation?¡ Respect¡ Contribute not used¡ Rights and welfare protected

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û Ideaû Question:¡ Population¡ Intervention, comparator¡ Outcome

û Literature search¡ Answered or not answered ¡ Reinventing the wheel?

û Protocolû Scientific and ethical reviewû Conductû Publication

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