Clinical Research• Observations• Relations• Question? Is there a relation between the time of car-oil change and • temperature?• Hypothesis? Increasing temperature decreases the time of car-oil change and temperature?
• Define measurement scales: – Temp: degrees centigrade – Time in minutes• Collect data• Test hypothesis 70 60 Temperature (oC) 50• Conclusion: 40 -increasing temp form 0-25 30 oC decreases time 20 10 -while increase above 25 oC 0 increases the time 0 10 20 30 Time (min) 40 50
Scientific research• Systematic investigation of hypothetical propositions about the presumed relations among observed phenomena.
Clinical research• Scientific research• On – humans or – materials or – data of human origin
Clinical research• Is there a relationship between Eczema and number of car-oil change in workers?• Number of car-oil change in workers – Limits: 16/day• Eczema – Limits: non-invasive (inspection and not biopsy) – Eczema score: area in CM x severity (0, 1, 2 3)
Why subjects engage in research? – To help their diseases – To help other patients – Other benefits: • e.g. payment Ahmed Zeeneldin 13
Is research beneficial to patients?• WE DO NOT KNOW: – It could be beneficial (Hopefully) – It could prove harmful – It could prove of no benefit Ahmed Zeeneldin 14
Research vs. routine practice• Practice: – Standard – approved – benefit• Research: may not always benefit: – Non-standard – Non-approved – Benefit? • May receive highest care • May directly benefit • May be harmed• Research gives Knowledge for better health• Individual: respect, safety and dignity Ahmed Zeeneldin 15
Study designs in health research• Observational: – No intervention• Experimental: – Intervention and outcome • Semi-experimental • True-Experimental Ahmed Zeeneldin 16
Study designs in Clinical Research• Observational: – Research – Not clinical trials• Experimental: – Research – As well as clinical trials Ahmed Zeeneldin 17
Observational studies• Cross-sectional• Case-control• Cohort Ahmed Zeeneldin 18
Cross-sectional studies• Example: – Obesity and Skin cancer •. Total SKIN cancer Obese 350 (70%) Non-Obese 150 (30%) Total 500 (100%) Ahmed Zeeneldin 19
Case-control studies• Example: – Lung cancer and smoking in Gharbia Lung cancer No-lung cancer Smoking 450 (90%) 150 (30%) No-smoking 50 (10%) 350 (70%) Total 500 500 Ahmed Zeeneldin 20
Cohort studies ﺟﻤﺎﻋﺔ• Example: – Skin cancer following chest wall irradiation for Breast cancer Breast CA+RT Breast CA- RT Skin cancer 10 (10%) 4 (1.3%) No-SKIN cancer 90 (90%) 296 (98.7%) Total 100 300 Ahmed Zeeneldin 21
Experimental Research Interventional Research• Phase I• Phase II• Phase III: – Randomized controlled trial (RCT)• Phase IV Ahmed Zeeneldin 22
Experimental Research Interventional Research• Phase I • Semi experimental• Phase II • Semi experimental• Phase III: • True experimental – Randomized controlled trial (RCT)• Phase IV Ahmed Zeeneldin 23
Example of clinical trials• Use of Nigella Sativa oil in treatment of metastatic malignant melanoma• اﺳﺗﺧدام زﯾت ﺣﺑﺔ اﻟﺑرﻛﺔ ﻓﻲ ﻋﻼج ﺳرطﺎن اﻟﺟﻠد اﻟﺻﺑﻐﻲ اﻟﻣﻧﺗﺷر
Question?• Why not going ahead and using this in all patients ? ~ 100, 000
Steps• Preclinical R – Lab: manufacturing and purification, solubility and preservation – Cell lines • Effective or not – Animals • Safe or not? – Dose and frequency and duration AND Route • Efficacious or not?• Clinical R – Safe or not? à phase I – Efficacious or not? à phase II – More effective than current chemotherapy? à phase III• What is next?
Why we use trials?• Animal and human trials• Predictability of safety and efficacy• Animals: – Safety prediction – Diseases are different in animals: X efficacy• Humans: – Safety and efficacy prediction• Prediction is never perfect Ahmed Zeeneldin 28
Preclinical Lab research• New viruses• New war weapons• Resistant microbes
Pre-clinical animal research• How long will guinea pig live in atmospheric temperature below 0°?• How long will a guinea pig live without food or water?• Carcinogenicity of car- oil on guinea pig skin?
Clinical research• How long will a human live in atmospheric temperature below 0°?• How long will a human live under a collapsed house without food or water?• This will decide the time rescuers will spend on searching?• Carcinogenicity of car-oil on human skin?
Clinical research• Are these trials acceptable?• Is this clinical research practice bad or good ?• BCRP• GCRP= GCP
Good Clinical Practice (GCP)• By GCP we mean: – Set of standards for clinical research – From design àconduct à monitoring/auditing à recording à analysis à reporting• Aspects of GCP – Science – Ethics – Quality
GCP1 Value (science), ،اﻟﻘﯾﻣﺔ2 Validity (quality), ﺻﻼﺣﯾﺔ3 Fairness (justice), اﻟﻌداﻟﺔ4 Risk– benefit ratio ﻧﺳﺑﺔ اﻟﻣﺧﺎطر واﻟﻣﻧﺎﻓﻊ (beneficence), ()اﻟﻣﻧﻔﻌﺔ5 Protocol and its اﻟﺑروﺗوﻛول Independent review, اﻟﻣراﺟﻌﺔ اﻟﻣﺳﺗﻘﻠﺔ6 Consent, اﻟﻣواﻓﻘﺔ اﻟﻣﺳﺗﻧﯾرة7 Respect اﻻﺣﺗرام (Emanuel et al. 2000) Belmont report, 1979.
GCP rules• Social and scientific Value: – respond to health needs and – provide a sound question whose answers will advance knowledge for the good of science and society.• Validity (Quality): – data generated from CR should be valid and interpretable through proper design, endpoints and methodology.• Fair subject selection: – being non-biased and based of scientific grounds.• Favorable risk– benefit ratio: – through minimization of vulnerability and risk as well as maximization of benefits.
• Independent review: – to ensure adherence to the ethical guidelines in design, conduct and analysis.• Informed consent: – the process that provides adequate information allows only voluntary participation. – Consent withdrawal should be allowed anytime in the research. – Consent does not deprive subjects from any of their rights nor does it alleviate researchers from their responsibilities in protecting safety, rights and welfare of subjects.• Respect for the enrolled subject’s: – autonomy, right and welfare both during and after research. – Individual’s rights and welfare should precede that of science and society
BCP (Bad Clinical Practice)• Does skin exposure to car- oil leads to skin cancer?• Orphan house• Deal with manager• Paint their skin with car-oil daily for 8 hours then wash• Do regular punch biopsied of the skin each month• Follow them without treatment for the rest of their lives
Good or badPoint Fulfill Bad Good mentValue √ Skin cancer following Skin cancer following exposure to car-oil exposure to car-oilValidity (design) X Artificial exposure Spontaneous natural exposureFair X Orphan house Oil station workersrisk– benefit ratio X No Tx allowed Tx allowedIndependent review X No YesConsent X No Yes Kids AdultsRespect X Withdrawal not allowed Withdrawal allowed
Historical background of GCP460 BC Oath of Hippocrates1930s U.S. Food, Drugs and Cosmetic Act1947 Nuremberg Code (following Nazi experiments in WWII)1948 Declaration of Human Rights1964 Declaration of Helsinki1979 The Belmont Report1982 International Guidelines for Biomedical Research Involving Human Subjects1996 ICH-GCP guidelines issued1997 ICH-GCP guidelines becomes law in some countries
Goals of GCP• To protect the rights, safety and welfare of humans participating in research• To assure the quality, reliability and integrity of data collected• To provide standards and guidelines for the conduct of clinical research
The 13 principles of ICH-GCP• Ethics: 1. Ethical conduct of clinical trials 2. Benefits justify risks 3. Rights, safety, and well-being of subjects prevail• Protocol and science: 4. Nonclinical and clinical information supports the trial 5. Compliance with a scientifically sound, detailed protocol
The 13 principles of ICH-GCP• Responsibilities: 6. IRB/IEC approval prior to initiation 7. Medical care/decisions by qualified physician 8. Each individual is qualified (education, training, experience) to perform his/her tasks• Informed Consent: 9. Freely given from every subject prior to participation
The 13 principles of ICH-GCP• Data quality and integrity: 10. Accurate reporting, interpretation, and verification 11. Protects confidentiality of records 12. Investigational Products Conform to GMP’s and used per protocol• Quality Control/Quality Assurance 13. Systems with procedures to ensure quality of every aspect of the trial
Summary• Scientific research• Clinical research• Clinical trials – Phase I, II, III and IV• Ethics in research• GCP: standards or guidelines to ensure research is scientific, ethical and of good quality• Parties involved in research and their role and responsibilities
Thank You Ahmed A ZeeneldinDirector of Research Center (RCENCI) Tel: 01111 000 943 Email: firstname.lastname@example.org Ahmed Zeeneldin 49