PCL WEEK 3&4

ETHICS AND CLINICAL RESEARCH

Definition of ethics:

  • Rights and responsibilities

  • Values pertaining to human conduct 

  • Right and wrong

  • Eg of ethical value: justice 

  • Nonmaleficence means to do no harm (does the benefit outweigh the burden)

  • Beneficence is action for benefit of others to help prevent harms

  • Non exploitation

  • Respect

  • Autonomy: the patient has own rights to your own body even if it differs from physicians 

Goals of clinical research 

  • Generalise knowledge to improve health and understand human bio 

Ethical requirements for clinical research

  • There can be a potential forexploitant in human subjects cause using them for the good of others 

  • But you want to minimise the possibility of exploitation (but it is always kind of there) 

Sources of guidance on ethical conduct

  • Internation documents

  • Declaration of Helsinki 

  • A lot of them were written in response to ethical events to prevent it 



Eg Historical events of ethical misconduct 

  1. Nuremberg code condemns atrocities of nazi physicians 

  2. Tuskegee study

  3. Declaration of Helsinki 

THE NUREMBERG CODE

  • Voluntary consent is essentials 



Guidelines for whether it's ethical or not:

  • Has 7 criteria 

  • Universal 

  • You can't lie to your volunteer 

  1. Value

  • Research has to be valuable with a goal of improving human health 

  • What isn't valuable: results that aren't generalizable, cant be an overlap of something that has been done before, unlikely to be disseminated, has to be practically implemented like not fancy

  • Value is important cause resources are limited, avoiding exploitation 

  • Is the intervention feasible?

  • Finite resources may be economic or scientific 

  1. Scientific Validity 

  • Rigorous methods, value can be great but designed or conducted poorly then thats bad cause have experienced people who arent thorough and cautious, results are invalid 

  • No purpose?

  • Methods have to be appropriate and feasible, clear scientific objective 

  • Lacking scientific study eg. too few subjects, sloppy conducting

  • If the outcome is already known then no point but also without scientific validity researcher wont know benefits which is a risk for subjects

  1. Fair subject selection

  • Which communities or types of people are approached

  • Efficiency cannot be more important than fairness

  • Recruiting strategy are seen by ethics boards 

  • Keep out people being high risk of being harmed

  • Some people may have the disease but can also enjoy the potential benefits 

  1. Favourable risk-benefit ratio:

  • 3 conditions:

    • Potential risk is minimised

    • The potential benefit is enhanced

    • Potential benefit to risk is proportionate

  • Identify risks and minimise them with research 

  • Specify potential benefits 

  • Could changes be made to increase the benefit 

  • Avoid extraneous benefits like financial or extra medical services that are unrelated 

  • Clinical research is NOT to provide health service

  • Make sure you communicate the hazards with other phases of clinical research 

  • Is the societal benefit being outweighed by the risk

  1. Independent review

  • Medical research interest isnt affecting the design 

  • Interest: advance their careers, quick research get funding

  • Study is reviewed by people who are unaffiliated to the study

  • Eg IRB or REB

  • Before a cynical trial begins they must be apporved by REB

  • Theyll check how youre recruiting, consent, risk benefit proportionality, confidentiality, fairness 

  1. Informed consent

  • participants making their own decisions for themselves

  • Ethical Principle of Autonomy 

  • As a subject confirm with doctors whether it's okay for you to do it

  • Consent is voluntary, informed, and ongoing

  • Structure of consent form: contact info, defined purpose, risks and benefits, confidentiality, voluntary consent, summary and signature that is witnessed

  1. Respect

  • Treated with respect even if subject doesnt want ot be a part any longer

  • If there's any new info let them know 

  • Look at adverse reactions

  • Let the subject know how they contributed 












Lecture 7 (week 4)

Clinical Trials

  • General Clinical Trials Overview

  • How to participate 

  • Phase 1 clinical trials overview

  • Pharmacokinetics 



Phase 1-3: premarket clinical trials in the drug discovery pipeline



Who conducts trials?

  • A company that develops the drug or they sponsor it and controls it (30%)

  • Actual trials in universities and private clinical research organization (70%)

  • Eg. princess margaret has a bunch of phase 1 clinical trials for cancer 

  • Trial has many locations 

  • Supervisors: medical doctor, expert



Where are phase 1 clinical trials held?

  • In proper institutions

  • Takes a long time- to monitor for safety

  • People get bored cause it takes times like days or weeks 



How to participate 

  • Websites 

  • Contact family doctor and they can refer you to them

  • Call them directly like ad 

  • They'll call you to see if you meet the requirements or are eligible through phone 

Inclusion criteria 

  • Goal of making sure that people in the trial are similar biologically eg healthy

  • Eg. no other medications, bmi, healthy and young

Exclusion criteria

  • Protect people who might be harmed by the study drug

  • Excluded, pregnnt women, people with adverse reaction, people with family history of disease

  • Then make appointment for screening visit, conse form and more info

  • Screening visit

    • Must meet strict entry requirement (inclusion and exclusion)

    • In person screening is more detailed

    • Physical exams and testing

    • Will the trial actually help yo? What are the known and potential risks and benefits? 

How to start phase 1 participation?

  • Contact CRO or hospital

Who is in phase 1 trial?

  • Healthy volunteers

  • Exception: cancer or oncolgy drugs

  • Risk of drugs like that on healthy volunteers is too high so use cancer patients 



Design of phase 1 clinical trials:

  • With the help of animal studies know the dose but usually use smaller amount then suggested by animal study

  • Start with much smaller doses in humans 

  • single ascending order, low to high 

  • Calculate a starting dose based on animal and then convert to human dose 

  • Slow and safe



Is a single dose of the drug safe?

  • Single ascending dose desing

  • Called a cohort 

  • Choose dosage and how many pills

  • How many people on dosage and placebo (they wouldnt know)

  • How many people Sentinel group and main group?

Are repeated doses safe?

  • Choose dosage and then change how many pills you give (like 5 over 5 days)

  • Why choose placebo? Some things may not be drug related, safety issues actually related to drug?



  • Phase 1 research question

 What doses are tolerable

Is it safe

How does the drug move in the body?

This result guides us to phase 2



How to tell if drug is safe?

  • Biomarkers? Test in blood and urine 

  • Things you can measure with number 

  • Eg. bp, tmp, cholesterol level, medical image, blood sugar, etc 

  • Cliincal signs like written document and observation




  • Adverse events  

  • Undesirable experiences 



  • serious Adverse events

  • Death

  • Life-threatening

  • Becoming hospiliazsed

  • Disability or permanent damage 



  • Is the safety in drug treated group the same as placebo group

  • Is the safety in 1 dose the same as multiple dose 



EG. clinical trial disaster phase 1

  • Drug to treat anxiety

  • Single ascending dose study for 64 volunteers 

  • 0.25 mg to 100 mg

  • Then sarted multiple ascending dose trials with each having 8 subjects eg. first group received 2.5 mg daily, the second 5 mg an the accident happened in the 5gh group which recieved 50 mg daily- highest dose

  • Serious AE: person brain dead, 5 in hospitals 

  • BUT WHY?

  • Gradual accumulation in brain which caused adverse reaction in later stage and not single dosage

  • Taught lesson and how to reduce accidents 

  • However the person who died had head concussion therefore selection process for volunteers should be VERY STRICT, check biomarkers before 



Phase 1 trials are generally safe and disaster is usual



Pharmacokinetics in phase 1

  • How it moves in body 

  • Frequent blood and urine tests to measure drug concentraion in bodily fluids 

  • Drug content in body and not getting digested by stomach

  • How quickly did body absorb it and how quickly body is eliminating (kidney or liver breaking ti down) 




Results of phase 1 studies

  • Early measure of safety and tolerability 

  • How does drug move in the body and how does dosage influence that