Principles of Ethics in Human Principles of Ethics in Human Research:Research:

Surgical Trials (& tribulations)Surgical Trials (& tribulations)

Lisa Schwartz, PhDLisa Schwartz, PhDArnold L Johnson Chair in Health Care EthicsArnold L Johnson Chair in Health Care Ethics

McMaster UniversityMcMaster UniversityCORE 2008CORE 2008

A Troubled HistoryA Troubled History

►Nuremberg & JapanNuremberg & Japan

►TuskegeeTuskegee

►Milgram experimentsMilgram experiments

►HeLa cell lineHeLa cell line

HistoryHistory

► The Tuskegee Syphilis Study remains one of The Tuskegee Syphilis Study remains one of the most outrageous examples of disregard the most outrageous examples of disregard of basic ethical principles of conduct (not to of basic ethical principles of conduct (not to mention violation of standards for ethical mention violation of standards for ethical research). In 1976, historian James Jones research). In 1976, historian James Jones (1981) interviewed John Heller, director of (1981) interviewed John Heller, director of the Venereal Diseases unit of the PHS from the Venereal Diseases unit of the PHS from 1943 to 1948. Among Heller's remarks were 1943 to 1948. Among Heller's remarks were the following: the following: "The men's status did not "The men's status did not warrant ethical debate. They were subjects, warrant ethical debate. They were subjects, not patients; clinical material, not sick not patients; clinical material, not sick people"people" ( (Bad BloodBad Blood; p. 179).; p. 179).

► Tuskegee University Tuskegee University http://www.tuskegee.edu/Global/Story.asp?s=1207598

The responseThe response► Nuremberg code Nuremberg code

http://www.med.nus.edu.sg/phar/sgcpp/nuremburg.htm ► Declaration of Helsinki Declaration of Helsinki www.wma.net ► CIOMS Statement CIOMS Statement http://www.cioms.ch/

► Tri-Council Policy Statement (Canada)Tri-Council Policy Statement (Canada)► National Committee on Ethics in Human Research National Committee on Ethics in Human Research

(Canada) (Canada) http://ncehr-cnerh.org/

► Belmont Report (US)Belmont Report (US)► Office of Human Research Protection (US) Office of Human Research Protection (US)

http://ohrp.osophs.dhhs.gov/index.html ► MRC guidelines MRC guidelines ((http://www.mrc.ac.uk/ethics http://www.mrc.ac.uk/ethics UK)UK)

► British Sociological Society (UK)British Sociological Society (UK)► Nuffield Reports (UK) Nuffield Reports (UK)

http://www.nuffieldbioethics.org/home/index.asp http://www.nuffieldbioethics.org/home/index.asp ► Research Ethics BoardsResearch Ethics Boards

ProblemsProblems

►They need to be interpreted They need to be interpreted

►Variability of applicationVariability of application

2 2 underpinning themesunderpinning themes

in human researchin human research

2 Underpinning Themes2 Underpinning Themes

-I--I-

The good of the manyThe good of the many

(the general good)(the general good)

The good of the fewThe good of the few

(individual interests)(individual interests)

Research is beneficial Research is beneficial

►Can bring benefits, goods, better lives, Can bring benefits, goods, better lives,

safer lives…safer lives…

►No argument there.No argument there.

►Research is a good thing.Research is a good thing.

Research entails risksResearch entails risks

►No research is risk freeNo research is risk free►Some risks can be anticipatedSome risks can be anticipated►Some risks can be mitigatedSome risks can be mitigated►Some risks can be avoidedSome risks can be avoided

►But because it is research we cannot But because it is research we cannot anticipate all risksanticipate all risks

Some Guiding PrinciplesSome Guiding Principles

►Respect for participants (living & not)Respect for participants (living & not)

►Beneficent intentionsBeneficent intentions

►UtilityUtility

►JusticeJustice

Consultation Draft of TCPSDecember 3, 2008 - March 31, 2009

►Updated & open for review at PRE website

► http://www.pre.ethics.gc.ca/english/newsandevents/newsreleases/draft_2nd_ed_of_TCPS.cfm

►New core principles:

concern for welfare;

respect for autonomy;

respect for equal moral status of all humans

Respect for ParticipantsRespect for Participants

►Respect for autonomy and human dignityRespect for autonomy and human dignity

► Informed ConsentInformed Consent

►HonestyHonesty

►Confidentiality fairly appliedConfidentiality fairly applied

►Fair recruitment proceduresFair recruitment procedures

►Follow upFollow up

►Collaborative researchCollaborative research

Ends, means, subjects and Ends, means, subjects and objectsobjects

There is a danger of reducing There is a danger of reducing

research subjects to research research subjects to research

objectsobjects

Edward WestonEdward Weston Nude Nude 19361936

© Center for Creative Photography, Arizona Board of Regents Scan courtesy of Masters of Photography© Center for Creative Photography, Arizona Board of Regents Scan courtesy of Masters of Photography

Edward Weston Edward Weston Shells Shells 1927 1927

© Center for Creative Photography, Arizona Board of Regents Scan courtesy of Masters of Photography© Center for Creative Photography, Arizona Board of Regents Scan courtesy of Masters of Photography

Ends, means, subjects and Ends, means, subjects and objectsobjects

►Be aware of the humanity in each Be aware of the humanity in each personperson

►Treat persons as ends in themselves Treat persons as ends in themselves and never solely as means to endsand never solely as means to ends

Recruitment and Consent

►Recruiting from among my own patients Ask an RA or resident to do the recruiting Be available for questions

►Do I need consent or REB approval for chart reviews? Yes, but it may be expedited.

►Can substitute decision makers consent for research? Sometimes

VulnerableVulnerable

►Special populationsSpecial populations Children, adolescents, Indigenous Children, adolescents, Indigenous

persons, marginalized, low income, persons, marginalized, low income, homeless, homeless,

►All research participantsAll research participants Because of the unknownBecause of the unknown

BeneficenceBeneficence

►Given that we will ask persons to take Given that we will ask persons to take risks for the benefit of others we must risks for the benefit of others we must do what we can do mitigate these risks do what we can do mitigate these risks and avoid them wherever possibleand avoid them wherever possible

►Duty to do goodDuty to do good►Duty to do good researchDuty to do good research►Duty to anticipate and avoid harmDuty to anticipate and avoid harm►TCPS: Balance Benefits and HarmsTCPS: Balance Benefits and Harms

Beneficence / Non-Beneficence / Non-MaleficenceMaleficence

► IntentionsIntentions

►OutcomesOutcomes

Balance the good of many with Balance the good of many with

the good of fewthe good of few

Minimal Harm ResearchMinimal Harm Research

UtilityUtility

►Make best use of scarce resourcesMake best use of scarce resources

►Research participants are a valuable Research participants are a valuable

resourceresource

►Ensure value of the research questionEnsure value of the research question

►Ensure quality of methodEnsure quality of method

US US Hearings on Human Hearings on Human Experimentation, Experimentation, 19731973

►““Those who have borne the brunt of Those who have borne the brunt of research – whether it is drugs or even research – whether it is drugs or even experimental surgery – have been the experimental surgery – have been the more disadvantaged people within our more disadvantaged people within our society; have been the institutionalised, society; have been the institutionalised, the poor, and minority members.” the poor, and minority members.”

►Sen. T Kennedy, prt 3, 7.3.1973, p. 841Sen. T Kennedy, prt 3, 7.3.1973, p. 841

Justice & InclusivenessJustice & Inclusiveness

►Given that risks cannot be avoided Given that risks cannot be avoided altogetheraltogether

► But are justified because of the benefits But are justified because of the benefits research confersresearch confers

► Justice asks us to share the burdens and Justice asks us to share the burdens and benefits of research fairlybenefits of research fairly

► Fair distribution of risksFair distribution of risks Do not over burden participantsDo not over burden participants

► Fair distribution of benefitsFair distribution of benefits Give everyone access to the benefits of being Give everyone access to the benefits of being

studied and of study outcomesstudied and of study outcomes

2 Underpinning Themes2 Underpinning Themes

-I--I-

Tension betweenTension between

the good of the manythe good of the many

(the general good)(the general good)

vsvs

The good of the fewThe good of the few

(individual interests)(individual interests)

2 Underpinning Themes2 Underpinning Themes

-II--II-

TrustTrust

& &

TrustworthinessTrustworthiness

TrustTrust

►TicketTicket

►KeyKey

Without trust…Without trust…

► The suspicion and fear generated by the Tuskegee The suspicion and fear generated by the Tuskegee Syphilis Study are evident today. Community Syphilis Study are evident today. Community workers report mistrust of public health institutions workers report mistrust of public health institutions within the African American community. Alpha within the African American community. Alpha Thomas of the Dallas Urban League testified before Thomas of the Dallas Urban League testified before the National Commission on AIDS: the National Commission on AIDS: "So many African "So many African American people I work with do not trust hospitals American people I work with do not trust hospitals or any of the other community health care service or any of the other community health care service providers because of that Tuskegee Experiment" providers because of that Tuskegee Experiment" (National Commission on AIDS, 1990).(National Commission on AIDS, 1990).

► http://www.tuskegee.edu/Global/Story.asp?s=1207598http://www.tuskegee.edu/Global/Story.asp?s=1207598

Academic Freedom & Academic Freedom & ResponsibilitiesResponsibilities

►Depends on trustworthiness and integrity Depends on trustworthiness and integrity

► honest and thoughtful inquiry, honest and thoughtful inquiry, ► rigorous analysis, rigorous analysis, ► accountability for the use of professional accountability for the use of professional

standardsstandards► the whole process should always be open to the whole process should always be open to

critical assessment and debatecritical assessment and debate

(TCPS)(TCPS)

Research Ethics BoardsResearch Ethics Boards

►The REB is your friendThe REB is your friend

►Element of peer reviewElement of peer review

►Protects participantsProtects participants

►Protects researchersProtects researchers

Special Issues for Research in Surgery?

►What is the difference between research and innovation? “Most surgeons innovate on a daily basis,

tailoring therapies and operations to the intrinsic uniqueness of every patient and their disease.” (quoted in Biffl et al)

►Is placebo (sham) surgery ethical?►Are trials designed to evaluate efficacy

of existing standards ethical?

Surgical Innovations Requiring Formal Review Surgical Innovations Requiring Formal Review (Biffl (Biffl et alet al))

If the innovation is planned*, AND:If the innovation is planned*, AND:

► The surgeon seeks to confirm a hunch or theory about The surgeon seeks to confirm a hunch or theory about the innovation;the innovation; OR:OR:

► The innovation differs significantly from currently The innovation differs significantly from currently accepted local practice;accepted local practice; OR:OR:

► Outcomes of the innovation have not been previously Outcomes of the innovation have not been previously described;described; OR:OR:

► The innovation entails potential risks for complications;The innovation entails potential risks for complications;

OR:OR:

► Specific or additional patient consent appears Specific or additional patient consent appears appropriate,appropriate,

► Then:Then:

a)a) The described review by a local surgical innovations The described review by a local surgical innovations committee is required, pluscommittee is required, plus

b)b) submission to the national innovations registry is submission to the national innovations registry is required,required, andand

c)c) additional informed consent is required of the patient additional informed consent is required of the patient specific to the nature of the proposed innovation.specific to the nature of the proposed innovation.

► *If an innovation *If an innovation occurred unplanned, occurred unplanned, it should be regarded it should be regarded as performed onas performed on

► an individual as-an individual as-needed basis for the needed basis for the benefit of that benefit of that particular patient, particular patient, unlessunless

► it meets any of the it meets any of the other five criteria. In other five criteria. In such instances, such instances, postoperatively, thepostoperatively, the

► patient or patient’s patient or patient’s surrogate should be surrogate should be informed of the informed of the innovative nature ofinnovative nature of

► the procedure. If it the procedure. If it does not meet any of does not meet any of the criteria, the the criteria, the innovation falls underinnovation falls under

► acceptable acceptable modifications of modifications of surgical technique.surgical technique.

When innovation becomes When innovation becomes research (Biffl et al)research (Biffl et al)

►““A systematic investigation, including A systematic investigation, including development, testing and evaluation, development, testing and evaluation, designed to develop or contribute to designed to develop or contribute to generalizable knowledge” generalizable knowledge”

►REB review is mandatory before the REB review is mandatory before the research begins.research begins.

Are placebos ethical?Are placebos ethical?““The NPWC agreed that as a general rule, research The NPWC agreed that as a general rule, research

subjects in the control group of a trial …should subjects in the control group of a trial …should receive an established effective therapyreceive an established effective therapy.”.”

► ““The use of placebos should remain firmly The use of placebos should remain firmly grounded in the grounded in the fiduciary obligations of fiduciary obligations of physicians towards patients physicians towards patients as formulated in as formulated in Article 3 of the Declaration of Helsinki.”Article 3 of the Declaration of Helsinki.”

► ""The Declaration of Geneva of the World Medical The Declaration of Geneva of the World Medical Association Association binds the physician with the words, binds the physician with the words, "the health of my patient will be my first "the health of my patient will be my first consideration.consideration.”’”’CIHR CIHR Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in

Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html

A placebo comparator is acceptable A placebo comparator is acceptable in the following situations:in the following situations:

► There are There are no established effective therapies no established effective therapies for the population and for the indication for the population and for the indication under study.under study.

► Existing Existing evidence raises substantial doubt evidence raises substantial doubt regarding the net therapeutic benefit of regarding the net therapeutic benefit of available therapies,available therapies,

► Patients are Patients are refractory refractory to the available therapies by virtue of their past treatment to the available therapies by virtue of their past treatment history or known medical history,history or known medical history,

► The study involves The study involves adding a new investigational therapy to establishedadding a new investigational therapy to established effective effective therapies, (established effective therapy + new therapy vs. established effective therapies, (established effective therapy + new therapy vs. established effective therapy + placebo) ,therapy + placebo) ,

► Patients have determined that the response to the established effective therapies for Patients have determined that the response to the established effective therapies for their condition is their condition is unsatisfactory unsatisfactory to them.to them.

► Patients have Patients have previously refusedpreviously refused established effective therapies for their condition." established effective therapies for their condition."

► * For articles (e) and (f) the determinations of response satisfaction and refusal of treatment must * For articles (e) and (f) the determinations of response satisfaction and refusal of treatment must take place take place outside of the context of recruitment outside of the context of recruitment for the clinical trial and prior to the offering of trial for the clinical trial and prior to the offering of trial participation to the potential subject, and be documented in a standardized manner. Under these participation to the potential subject, and be documented in a standardized manner. Under these conditions, study subjects would not necessarily be considered "refractory" to the available therapies conditions, study subjects would not necessarily be considered "refractory" to the available therapies since the choice to discontinue available therapies is based on their own opinion and values, not since the choice to discontinue available therapies is based on their own opinion and values, not those of the clinicians responsible for their care. As such, regulatory approval of the therapy under those of the clinicians responsible for their care. As such, regulatory approval of the therapy under investigation would not necessarily be restricted.investigation would not necessarily be restricted.

CIHR CIHR Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html

EquipoiseEquipoise

►Ethical acceptability of placebo requires Ethical acceptability of placebo requires clinical equipoiseclinical equipoise

►"Clinical equipoise means a genuine "Clinical equipoise means a genuine uncertainty on the part of the expert uncertainty on the part of the expert medical community about the comparative medical community about the comparative therapeutic merits of therapeutic merits of each arm each arm of a clinical of a clinical trial.”trial.”

►According to the collective wisdom of According to the collective wisdom of expert practitioners.expert practitioners.

CIHR CIHR Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html

History & the Fiduciary DutyHistory & the Fiduciary Duty

► ““the members of the ethics subcommittee the members of the ethics subcommittee believe that the duty of the clinician in clinical believe that the duty of the clinician in clinical research is the same as that of the clinician research is the same as that of the clinician outside of clinical research. The committee outside of clinical research. The committee supports this principle as fundamental, rooted supports this principle as fundamental, rooted not only in traditional medical ethics but also not only in traditional medical ethics but also equally in the reflection of tragic recurrent equally in the reflection of tragic recurrent experiences which occur when physicians forget experiences which occur when physicians forget or deny their inalienable obligations to their or deny their inalienable obligations to their patients”.patients”.

CIHR CIHR Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html

M.H. Pappworth in 1967M.H. Pappworth in 1967

►““No physician is justified in placing No physician is justified in placing science or the public welfare first and science or the public welfare first and his obligation to the individual, who is his obligation to the individual, who is his patient or subject, second. No his patient or subject, second. No doctor, however great his capacity or doctor, however great his capacity or original his ideas, has the right to original his ideas, has the right to choose martyrs for science or for the choose martyrs for science or for the general good.”general good.”

►Pappworth M.H. Human Guinea Pigs; Boston: Pappworth M.H. Human Guinea Pigs; Boston: Beacon Press, 1967; pg. 27Beacon Press, 1967; pg. 27

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152.152.► Biffl W. et al 2008 “Responsible Development and Application of Surgical Innovations: A Biffl W. et al 2008 “Responsible Development and Application of Surgical Innovations: A

position statement of the society of university surgeons”. position statement of the society of university surgeons”. Journal of the American College of Journal of the American College of SurgeonsSurgeons; 206:6 1205-1209. ; 206:6 1205-1209.

► Beauchamp T L, Childress J F, 1994 Beauchamp T L, Childress J F, 1994 The principles of biomedical ethicsThe principles of biomedical ethics, 4th edn. Oxford , 4th edn. Oxford University PressUniversity Press

► CIHR CIHR Final Report of the National Placebo Working Committee on the Appropriate Use of Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html Placebos in Clinical Trials in Canada (July 2004) http://www.cihr-irsc.gc.ca/e/25139.html

► Centre for Disease Control and Prevention Centre for Disease Control and Prevention http://www.cdc.gov/nchstp/od/tuskegee/time.htm#tophttp://www.cdc.gov/nchstp/od/tuskegee/time.htm#top

► Health Care Consent Act Ontario, 1996Health Care Consent Act Ontario, 1996 ► Hornblum, Allen M 1998 Hornblum, Allen M 1998 Acres of SkinAcres of Skin. Routledge, NY. Routledge, NY► Morgenstern L 2008 “Can surgical research be ethical?” Morgenstern L 2008 “Can surgical research be ethical?” Surgical Innovation Surgical Innovation 15:3 157-160.15:3 157-160.► MRC guidelines for good clinical practice in clinical trials 1998. http://www.mrc.ac.uk/ethics MRC guidelines for good clinical practice in clinical trials 1998. http://www.mrc.ac.uk/ethics ► Pappworth M H 1990 "Human Guinea Pigs"- a history. Pappworth M H 1990 "Human Guinea Pigs"- a history. British Medical Journal British Medical Journal 301:1456-301:1456-

1460 1460 ► Pappworth M H 1967 Pappworth M H 1967 Human Guinea PigsHuman Guinea Pigs. Beacon Press, Boston. Beacon Press, Boston► Ross, S et al 2008 “Ethical issues associate with the introduction of new surgical devices, or Ross, S et al 2008 “Ethical issues associate with the introduction of new surgical devices, or

just because we ca, doesn’t mean we should” just because we ca, doesn’t mean we should” Jrl of Obstetrics and Gynaecology of Canada Jrl of Obstetrics and Gynaecology of Canada 30(6):508-513. 30(6):508-513.

► Tri-Council Policy Statement Tri-Council Policy Statement http://www.pre.ethics.gc.ca/english/policystatement/policystatement.cfm http://www.pre.ethics.gc.ca/english/policystatement/policystatement.cfm

► Uris L, 1992 Uris L, 1992 QB VII QB VII Harper Collins LondonHarper Collins London

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Respect for personsRespect for persons

►TCPS TCPS Respect for Human DignityRespect for Human Dignity Free and Informed ConsentFree and Informed Consent Privacy and ConfidentialityPrivacy and Confidentiality

Subjects are not objectsSubjects are not objects