Research Using Human Subjects notes PDF

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Research Using Human Subjects Legal Cases • Halushka v. U. of Saskatchewan (1965) 53 D.L.R. (2D) 436 • Full standard of disclosure • Weiss v. Solomon (1989) 48 C.C.L.T. 280 (Que.S.C.) • All risks must be disclosed, even remote ones – especially if they involve serious consequences. (standard comprehension) Central Issues: • Consent ▫ Competent persons ▫ Incompetent persons • Reason/need for experimenting • Reward/remuneration for participation • Right to participate • Ethical limits of experimentation • Funding and control of research History: • Ibn Sina Canon of Medicine (1025) ▫ First introduction of systematic scientific experimentation in medicine ▫ Associated with ethical guidelines • Some unethical experiments ▫ Jenner smallpox experiment ▫ Tuskegee (1932-72) • Syphilis/baseline • Undue enticement • Doses of polluted penecillin ▫ Nazi Germany (1940's) ▫ Japan (1940's) • Frozen organs ▫ Allied Experiments (1940's) ▫ Allen Memorial Institute (Montreal, 1950's) • Brain washing – “treatment” for medical mental issues (depression) • LSD, sleep for 30/40 days • Edited videos of them saying negative things about themselves ▫ Willowbrook (1970's) • New York, mentally disabled children to infect with hepatitis to see if something would help Modern Codes and Guidelines • Nuremberg Code (1947) • Trials of War Criminals before the Nuremberg Military Tribunal (1948) • first international code dealing with human experimentation • competent and voluntary consent is absolute condition  but does not apply to those without the capacity to consent • laid foundation for later codes • since then modified to be less strict WMA Declaration of Helsinki (1964 – 2012) • substitute decision makers can consent for those without capacity

WHO Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products (1996) • Convention on Human Rights and Biomedicine (Council of Europe 1997) • Guidelines for Research Involving Human Subjects [Tri-Council (MRC, SSHRC, ECC, 1998)] ▫ Any human research governed by . only those who receive funds from the provincial and ___ or else no $$ Experimentation • Types of experimentation ▫ Non-human animals ▫ Human animals ▫ Tissues and biological samples ▫ Cadavers ▫ Computer models Why Experiment? • Fiduciary obligation of HC professionals ▫ Failure to conduct controlled and scientifically valid experiment means that treatment is an uncontrolled experiment • Reliance on “traditional” knowledge and techniques is subject to nature of transmission itself  Influenced by socio-cultural parameters  Cannot rule out placebo effect (brain influences body) Right Vs. Duty to Participate in Experiments • Free rider problem Requirement of Consent: • Voluntary • No undue enticement • Complete disclosure ▫ Halushka v. University of Saskatchewan • Assent by incompetent subjects ▫ Consent of incompetent subjects is enabling ▫ Refusal of assent by incompetent subjects is binding Ethical Requirement for experimentation/Clinical Trails:  Value  must enhance knowledge or health,  Subject selection  must be fair, objective, representative,  Review  must be independently reviewed,  Informed consent  : voluntary, competent and informed.  Respect  must safeguard privacy, respect values etc. of subjects.  EXPERIMENTAL EQUIPOISE (null hypothesis)  Since the experimental subject is exposed to risk, there must be genuine uncertainty as to which treatment is better: the new one or some established one.  MONITORING OF DATA

Closeness to the protocol may blind unbiased perception of data. Consequently a datamonitoring officer is ethically appropriate. SCIENTIFIC VALIDITY  Since the experimental subject is exposed to risk, fidelity/integrity entails that the protocol must be scientifically valid  Scientifically valid is not ethically defensive  Can’t use subjective research for generalizing results ACCEPTABLE RISK/BENEFIT RATIO  Since the experimental subject is exposed to risk, there is an ethical obligation to ensure that the risk be defensible in terms of the overall aim.  Risks must not outweigh the untreated condition 

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Equipoise • Theoretical ▫ The experimental data do not favour one modality over another. • Clinical ▫ There is genuine disagreement among reasonably qualified professionals over the effectiveness, of the relevant modality. ▫ How data functions applied in real life different because research cannot control everything Experimentation • Therapeutic: an attempt to help the patient • Non-therapeutic: to find out data Types of Trials/Experiments:  Phase I: Safety Screening (non-therapeutic) - establish the safety of the drug and determine the toxicity levels. - usually on healthy volunteers - often paid - Small number (~ 15 – 90)  Phase II: Establishing the Protocol (how effective) - refine - usually on patient-group that is supposed to benefit from the drug - establish proper experimental conditions for Phase III trials (e.g.. End-points aimed at) - introduction of control groups and placebos - Larger numbers (~80 – 250) - Continue to monitor safety  Phase III: Trials on patients (confirmation or disproof) - large patient pool on whom drug is tried (thousands, frequently multi-centred), representative of the population - usually two large “pivotal” studies needed for approval  Phase IV trials - Frequently called post-marketing surveillance studies - Essentially voluntary - Done after has been licensed for sale (after has received Notice of Compliance) - Health Products and Food Branch, Health Canada as responsible agency Distinct Legislation – DO NOT HAVE TO KNOW Food and Drug act - federal, certificate of compliance for drugs For medications 9 http://laws.justice.gc.ca/en/F-27/ Have to be liscenced,

Placebos  "any therapy or component of therapy that is deliberately used for its non-specific, psychological or psycho-physical effect, or that is used for its presumed specific effect but is without specific activity for the condition being treated."  are uncontrollable, yet, 35-40% rely on placebo effect in medical office  Data doesn’t support reactive placebos  The existence of clinical equipoise results in a situation where the physician-researcher does not jeopardize the duty to beneficence.  The risks associated with the use of placebos directly determine their ethical acceptability.  The scientific need for the placebo legitimates its use.  Placebo use is unethical, it is a lie = paternal relationship o However, the professional can say there is no data and that it may or may not work Useable Studies (old), are valid.  Beecher HK. The powerful placebo. JAMA 1955;159:1602-1606. o pain medication placebo effect on soldiers from WWII and Korea o Soldiers prescribed pain medication. If they were expecting to go back to battle, the solider would require higher pain medication than those who do not expect to go back to battle o The mind and how you experience/perceive pain  McDonald CJ, Mazzuca SA. How much of the placebo "effect" is really statistical regression? Stat Med 1983;2:417-427  Meta-analysis reported 2 – 9.9 %  Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001 Jul 26;345(4):304.  Meta-analysis reported essentially no effect  Dorn SD, Kaptchuk TJ, Park JB, Nguyen LT, Canenguez K, Nam BH, Woods KB, Conboy LA, Stason WB, Lembo AJ. A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome. Neurogastroenterol Motil. 2007 Aug;19(8):630-7.  Meta-analysis showed 42.6% (95% confidence interval, 38.0-46.5%).  Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet 2010 Feb 20;375(9715):686-95. Placebo Use in therapeutic contexts gives the illusion there is a pill for everything. Encourages that idea that if there is something is wrong, it has a cure. Experimental: deception only when necessary, and therefore in the consent protocol you must be told you may be in the placebo group. In addition to the use of a cross over Innovative Treatment  Treatment that has been established in other places but not been used that particular setting  Treatment where the parameters have not been established for this type of setting  Licensed drugs are legally prescribe-able by HC professionals, however something must be prescribed for something it is not immediately meant for. o This is an uncontrolled experiment essentially Controversies _ DO NOT HAVE TO KNOW (slide 29) If there is no treatment for a particular US house ways and means committee?? Is there consent when there is no treatment and unsure of Example: Ebola and Z-Map treatment. Drug may make it worse.

Ethical concern; is it really possible to get informed consent No resolved Forbidden Fruit Doctrine – “is it unethical to use data that was derived unethically?” Con argument: using the data validates an unethical approach to get the data and therefore may encourage unethical experiments. It further violates the humanity of the victims Pro argument: if a professional has a fiduciary obligation to help a patient with a known treatment (that was derived unethical) it would violate the fiduciary obligation for them to not employ that treatment Consent: *** General rule: consent must be obtained by person conducting the study or someone is equally knowledgeable.  Signing the form is not consent – the process behind it is important – standard of comprehension and standard of standard of comprehension- reibel v hughes, Standard of disclosure – halushka vs u.s.  Recruiting from own patient population is unethical o Compromise o Power relationship Assent vs. Consent: • Consent for all competent populations • Assent for all compromised populations ▫ Assent is enabling ▫ Refusal of assent is binding Compromised Populations  Children – BUT capacity?  AC v. Manitoba – if child has capacity; can give consent, depends on capacity  Incarcerated = compromised (undue enticement) o controlled population, controlled variables  In need/dependent populations o belief they will get reward or help.  Next of kin, friends, or emotionally connected person  Persons in dependent power relationship Compromised Populations • McCormick – if compromised populations are unused, there will be no data for them. Compromised populations are populations that benefit from healthcare so if they do not contribute, they are free riders. o Children should enrolled in non-therapeutic experiments with minimal risk as they are beneficiaries and have an obligation of social embedding • Ramsey – compromised populations need protection o Children should not be used in non-therapeutic experiments because “utter helplessness demands utter protection” Tri Council Policy Statement/Guidelines • Promulgated in 1998 • Guidelines apply to all research in Canada that is PUBLICALLY FUNDED o medical, social, engineering, etc. • Does not apply legally to privately funded research or experimentation, however, the guidelines will still be relevant in court (quasi-judicial body)(legal standard)

The rules and opinions have judicial force for measurement Effective legal standing Quasi – can’t make laws, makes rules referenced in legislation Principles Appealed to by the Tri-Coucil (fundamental to guidelines – not all are ethical principles)  Respect for human dignity  Respect for free and informed consent  Respect for vulnerable persons (special care for compromised populations)  Respect for privacy and confidentiality (is a right and duty and must be maintained). o Persons must be told: what data is gathered, why, how it is protected, etc (in book) o Can withdraw at anytime including the destruction of data if possible o If it will ever be used for secondary use (must contact and regain consent for new use)  Respect for justice and inclusiveness  Balancing harms and benefits  Minimizing Harm  Maximizing benefit Concept of Minimal Risk • central to the Tri-Council's Guidelines • badly defined : "no greater than what is encountered by subject in those aspects of everyday life that relate to the research" • danger of "venue-shopping" concept of proportionate review • "the more invasive the research, the greater should be the care in assessing the research" • is too limited in that it ignores potential psychological harm deception • Nature of result to be obtained • Necessity of using deception • Possibility of debriefing without permanent harm ▫ Milgram “Obedience to Authority” The Rules apply to: • all federal agencies and departments • all agencies that receive federal funding • all individuals who receive federal funding Research and Industry • Ethical issues ▫ Funding and expectations of control  of information / data  Olivieri case  of product  of venues ▫ Orphan drugs Funding and expectations - data that is publically funded should be publically available Olivieri – someone did not want to disclose the negative effects and she wanted to share it. Most universities want the funding so was on their side. – went to court, olivieri won Consent and collectivities ** Proper consent from the individual and their society

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Disparity between politically correct and ethically acceptable rules ▫ Tradition is not itself an ethical justification ▫ Relevance of S. 15 of the Charter - is unethical (right to determination) – violates s. 15 of the Charter...