CIOMS International Ethical Guidelines for Biomedical Resear

8/20/2019 CIOMS International Ethical Guidelines for Biomedical Resear

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Council for International Organizations of Medical Sciences(CIOMS)

International EthicalGuidelines for BiomedicalResearch Involving HumanSubjects

The Council for InternationalOrganizations of Medical Sciences(CIOMS) announces the publicationof its revised/updated InternationalEthical Guidelines for BiomedicalResearch Involving HumanSubjects.

This 22 te!t supersedesthe "##$ %uidelines. It is the third inthe series of bio&edical'researchethical guidelines issued b CIOMSsince "#2. Its core consists of 2"guidelines *ith co&&entaries. +prefator section outlines thehistorical bac,ground and therevision process- and includes anintroduction- an account of earlierinstru&ents and guidelines- astate&ent of ethical principles and aprea&ble. +n +ppendi! lists the

ite&s to be included in the researchprotocol to be sub&itted for

The %uidelines relate&ainl to ethical justification andscientific validity of research; ethical review; informed consent;vulnerability of individuals, grous,communities and oulations;women as research subjects; e!uity regarding burdens and benefits;choice of control in clinical trials;confidentiality; comensation forinjury; strengthening of national orlocal caacity for ethical review;and obligations of sonsors to rovide health"care services#

Their scope reflects thechanges- the advances and thecontroversies that havecharacterized bio&edical researchethics in the last t*o decades. i,ethose of "#2 and "##$- the 22

CIOMS %uidelines are designed tobe of use to countries in definingnational policies on the ethics ofbio&edical research involvinghu&an subects- appling ethicalstandards in local circu&stances-and establishing or i&provingethical revie* &echanis&s. +particular ai& is to reflect theconditions and the needs of lo*'resource countries- and thei&plications for &ultinational ortransnational research in *hich the

&a be partners.

IS01 #2 #$ 34 4

5rice6 S*iss francs 2.

Order fro& CIOMS-c/o 78O- +venue +ppia 2-C8"2"" %eneva 23- S*itzerland.

9'&ail6 cio&s:*ho.int


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scientific and ethical revie* andclearance. +ppendices include alsothe 7orld Medical +ssociation;s" 22) 3#" $> "$?a!6 (=>" 22) 3#" >2

International Ethical Guidelines for Biomedical Research

Involving Human Subjects

Prepared by the Council for International rgani!ations of "edical Sciences

#CI"S$ in collaboration %ith the &orld Health rgani!ation #&H$

CI"SGeneva

'(('

C)*E)*S

+C,)&-E.GE"E)*S

B+C,GR/).

I)*R./C*I)

I)*ER)+*I)+- I)S*R/"E)*S +). G/I.E-I)ES

GE)ER+- E*HIC+- PRI)CIP-ES

PRE+"B-E

*HE G/I.E-I)ES

Ethical justification and scientific validity of biomedical research involving human

subjects

Ethical review

Ethical revie% committees

Ethical revie% of e0ternally sponsored research

Informed consent

Individual informed consent

btaining informed consent1 Essential information for prospective research subjects

btaining informed consent1 bligations of sponsors and investigators

Inducement to participate

Benefits and ris2s of study participation


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Special limitations on ris2 %hen research involves individuals %ho are not capable of

giving informed consent

3 3 3 3 3

Research in populations and communities %ith limited resources

3 3 3 3 3Choice of control in clinical trials

Vulnerable groups

E4uitable distribution of burdens and benefits in the selection of groups of subjects in

research

Research involving vulnerable persons

Research involving children

Research involving individuals %ho by reason of mental or behavioural disorders are

not capable of giving ade4uately informed consent

Women as research participants

&omen as research participants

Pregnant %omen as research participants

3 3 3 3 3

Safeguarding confidentiality

Right of injured subjects to treatment and compensation

Strengthening capacity for ethical and scientific revie% and biomedical research

Ethical obligation of e0ternal sponsors to provide health5care services

+ppendi0 61 Items to be included in a protocol #or associated documents$ for

biomedical research involving human subjects7

+ppendi0 '1 *he .eclaration of Helsin2i

+ppendi0 81 *he phases of clinical trials of vaccines and drugs

+C,)&-E.GE"E)*S

*he Council for International rgani!ations of "edical Sciences #CI"S$ac2no%ledges the substantial financial contribution of the 9oint /nited )ations

Programme on HI:;+I.S #/)+I.S$ to the preparation of the '((' International

Ethical Guidelines for Biomedical Research Involving Human Subjects7 *he &orld

Health rgani!ation in Geneva contributed generously also through the departments of

Reproductive Health and Research< Essential .rugs and "edicines Policy< :accines and

Biologicals< and HI:;+I.S;Se0ually *ransmitted Infections< as %ell as the Special

Programme for Research and *raining in *ropical .iseases7 CI"S %as at all times

free to avail of the services and facilities of &H7

CI"S ac2no%ledges also %ith much appreciation the financial support to the project

from the Government of =inland< the Government of S%it!erland< the S%iss +cademy


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of "edical Sciencesor2 in 9anuary '((6 and continued for several months to interact electronically

%ith one another and %ith the secretariat to prepare the third draft< posted on theCI"S %ebsite in 9une '((61 =ernando -olas Step2e #chair$< 9ohn Bryant< -eonardo de

Castro< Robert -evine< Ruth "ac2lin< and Godfrey *ang%a? the group continued from

ctober '((6< together %ith =lorencia -una and Rodolfo Saracci< to cooperate in

preparing the fourth draft7 *he contribution of this group %as invaluable7

*he interest and comments of the many organi!ations and individuals %ho responded to

the several drafts of the guidelines posted on the CI"S %ebsite or other%ise made

available are gratefully ac2no%ledged #+ppendi0 @$

+t CI"S< Sev =luss %as at all times ready and resourceful %hen consulted< %ith

advice and constructive comment< and "rs ,athryn Chalaby5+msler responded most

competently to the sometimes considerable demands made on her administrative and

secretarial s2ills7

B+C,GR/).

*he Council for International rgani!ations of "edical Sciences #CI"S$ is an

international nongovernmental organi!ation in official relations %ith the &orld Health

rgani!ation #&H$7 It %as founded under the auspices of &H and the /nited )ations Educational< Scientific and Cultural and rgani!ation #/)ESC$ in 6AA %ith

among its mandates that of maintaining collaborative relations %ith the /nited )ations

and its speciali!ed agencies< particularly %ith /)ESC and &H7

CI"S< in association %ith &H< undertoo2 its %or2 on ethics in relation to

biomedical research in the late 6A(s7 +t that time< ne%ly independent &H "ember

States %ere setting up health5care systems7 &H %as not then in a position to promote

ethics as an aspect of health care or research7 It %as thus that CI"S set out< in

cooperation %ith &H< to prepare guidelines D to indicate ho% the ethical principles

that should guide the conduct of biomedical research involving human subjects< as set

forth in the .eclaration of Helsin2i< could be effectively applied< particularly indeveloping countries< given their socioeconomic circumstances< la%s and regulations


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and e0ecutive and administrative arrangementsD7 *he &orld "edical +ssociation had

issued the original .eclaration of Helsin2i in 6A@ and an amended version in 6A7

*he outcome of the CI"S;&H underta2ing %as< in 6AF'


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committee< %hich met in "ay 6AAA7 *he committee proposed amendments and listed

topics on %hich ne% or revised guidelines %ere indicated? it recommended papers to be

commissioned on the topics< as %ell as authors and commentators< for presentation and

discussion at a CI"S interim consultation7 It %as considered that an interim

consultation meeting< of members of the steering committee together %ith the authors of

commissioned papers and designated commentators< follo%ed by further redrafting andelectronic distribution and feedbac2< %ould better serve the purpose of the project than

the process originally envisaged< %hich had been to complete the revision in one further

step7 *he consultation %as accordingly organi!ed for "arch '(((< in Geneva7

+t the consultation< progress on the revision %as reported and contentious matters

revie%ed7 Eight commissioned papers previously distributed %ere presented<

commented upon< and discussed7 *he %or2 of the consultation continued %ith ad hoc

electronic %or2ing groups over the follo%ing several %ee2s< and the outcome %as made

available for the preparation of the third draft7 *he material commissioned for the

consultation %as made the subject of a CI"S publication1 Biomedical Research

Ethics !pdating International Guidelines. " #onsultation #.ecember '((($7

+n informal redrafting group of eight< from +frica< +sia< -atin +merica< the /nited

States and the CI"S secretariat met in )e% >or2 City in 9anuary '((6< and

subse4uently interacted electronically %ith one another and %ith the CI"S secretariat7

+ revised draft %as posted on the CI"S %ebsite in 9une '((6 and other%ise %idely

distributed7 "any organi!ations and individuals commented< some e0tensively< some

critically7 :ie%s on certain positions< notably on placebo5controlled trials< %ere

contradictory7 =or the subse4uent revision t%o members %ere added to the redrafting

group< from Europe and -atin +merica7 *he conse4uent draft %as posted on the %ebsite

in 9anuary '((' in preparation for the CI"S Conference in =ebruary; "arch '(('

*he CI"S Conference %as convened to discuss and< as far as possible< endorse a final

draft to be submitted for final approval to the CI"S E0ecutive Committee7 Besides

representation of member organi!ations of CI"S< participants included e0perts in

ethics and research from all continents7 *hey revie%ed the draft guidelines seriatim and

suggested modifications7 Guideline 66< #hoice of control in clinical trials< %as redrafted

at the conference in an effort to reduce disagreement7 *he redrafted te0t of that

guideline %as intensively discussed and generally %ell received7 Some participants<

ho%ever< continued to 4uestion the ethical acceptability of the e0ception to the general

rule limiting the use of placebo to the conditions set out in the guideline? they argued

that research subjects should not be e0posed to ris2 of serious or irreversible harm %henan established effective intervention could prevent such harm< and that such e0posure

could constitute e0ploitation7 /ltimately< the commentary of Guideline 66 reflects the

opposing positions on use of a comparator other than an established effective

intervention for control purposes7

*he ne% te0t< the '((' te0t< %hich supersedes that of 6AA8< consists of a statement of

general ethical principles< a preamble and '6 guidelines< %ith an introduction and a brief

account of earlier declarations and guidelines7 -i2e the 6AF' and 6AA8 Guidelines< the

present publication is designed to be of use< particularly to lo%5resource countries< in

defining national policies on the ethics of biomedical research< applying ethical

standards in local circumstances< and establishing or redefining ade4uate mechanismsfor ethical revie% of research involving human subjects


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Comments on the Guidelines are %elcome and should be addressed to the Secretary5

General< Council for International rgani!ations of "edical Sciences< c;o &orld Health

rgani!ation< CH56'66 Geneva '< S%it!erland? or by e5mail to cioms%ho7int

I)*R./C*I)

*his is the third in the series of international ethical guidelines for biomedical research

involving human subjects issued by the Council for International rgani!ations of

"edical Sciences since 6AF'7 Its scope and preparation reflect %ell the transformation

that has occurred in the field of research ethics in the almost 4uarter century since

CI"S first undertoo2 to ma2e this contribution to medical sciences and the ethics of

research7 *he CI"S Guidelines< %ith their stated concern for the application of the

.eclaration of Helsin2i in developing countries< necessarily reflect the conditions and

the needs of biomedical research in those countries< and the implications for

multinational or transnational research in %hich they may be partners7

+n issue< mainly for those countries and perhaps less pertinent no% than in the past< has

been the e0tent to %hich ethical principles are considered universal or as culturally

relative the universalist versus the pluralist vie%7 *he challenge to international

research ethics is to apply universal ethical principles to biomedical research in a

multicultural %orld %ith a multiplicity of health5care systems and considerable variation

in standards of health care7 *he Guidelines ta2e the position that research involving

human subjects must not violate any universally applicable ethical standards< butac2no%ledge that< in superficial aspects< the application of the ethical principles< e7g7< in

relation to individual autonomy and informed consent< needs to ta2e account of cultural

values< %hile respecting absolutely the ethical standards7

Related to this issue is that of the human rights of research subjects< as %ell as of health

professionals as researchers in a variety of sociocultural conte0ts< and the contribution

that international human rights instruments can ma2e in the application of the general

principles of ethics to research involving human subjects7 *he issue concerns largely<

though not e0clusively< t%o principles1 respect for autonomy and protection of

dependent or vulnerable persons and populations7 In the preparation of the Guidelines

the potential contribution in these respects of human rights instruments and norms %asdiscussed< and the Guideline drafters have represented the vie%s of commentators on

safeguarding the corresponding rights of subjects7

Certain areas of research are not represented by specific guidelines7 ne such is human

genetics7 It is< ho%ever< considered in Guideline 6F Commentary under Issues of

confidentialit$ in genetics research. *he ethics of genetics research %as the subject of a

commissioned paper and commentary7

+nother unrepresented area is research %ith products of conception #embryo and fetal

research< and fetal tissue research$7 +n attempt to craft a guideline on the topic proved

unfeasible7 +t issue %as the moral status of embryos and fetuses and the degree to%hich ris2s to the life or %ell5being of these entities are ethically permissible7


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In relation to the use of comparators in controls< commentators have raised the the

4uestion of standard of care to be provided to a control group7 *hey emphasi!e that

standard of care refers to more than the comparator drug or other intervention< and that

research subjects in the poorer countries do not usually enjoy the same standard of all5

round care enjoyed by subjects in richer countries7 *his issue is not addressed

specifically in the Guidelines7

In one respect the Guidelines depart from the terminology of the .eclaration of

Helsin2i7 Best current interventionJ is the term most commonly used to describe theactive comparator that is ethically preferred in controlled clinical trials7 =or many

indications< ho%ever< there is more than one established currentJ intervention and

e0pert clinicians do not agree on %hich is superior7 In other circumstances in %hich

there are several established currentJ interventions< some e0pert clinicians recogni!e

one as superior to the rest? some commonly prescribe another because the superior

intervention may be locally unavailable< for e0ample< or prohibitively e0pensive or

unsuited to the capability of particular patients to adhere to a comple0 and rigorous

regimen7 Established effective interventionJ is the term used in Guideline 66 to refer toall such interventions< including the best and the various alternatives to the best7 In some

cases an ethical revie% committee may determine that it is ethically acceptable to use an

established effective intervention as a comparator< even in cases %here such an

intervention is not considered the best current intervention7

*he mere formulation of ethical guidelines for biomedical research involving human

subjects %ill hardly resolve all the moral doubts that can arise in association %ith much

research< but the Guidelines can at least dra% the attention of sponsors< investigators

and ethical revie% committees to the need to consider carefully the ethical implications

of research protocols and the conduct of research< and thus conduce to high scientific

and ethical standards of biomedical research7

I)*ER)+*I)+- I)S*R/"E)*S +). G/I.E-I)ES

*he first international instrument on the ethics of medical research< the )uremberg

Code< %as promulgated in 6A as a conse4uence of the trial of physicians #the .octorsJ

*rial$ %ho had conducted atrocious e0periments on unconsenting prisoners anddetainees during the second %orld %ar7 *he Code< designed to protect the integrity of

the research subject< set out conditions for the ethical conduct of research involving

human subjects< emphasi!ing their voluntary consent to research7

*he /niversal .eclaration of Human Rights %as adopted by the General +ssembly of

the /nited )ations in 6AF7 *o give the .eclaration legal as %ell as moral force< the

General +ssembly adopted in 6A@@ the International Covenant on Civil and Political

Rights7 +rticle of the Covenant states D %o one shall be subjected to torture or to

cruel& inhuman or degrading treatment or punishment. In particular& no one shall be

subjected without his free consent to medical or scientific e'perimentation(. It is

through this statement that society e0presses the fundamental human value that is held


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to govern all research involving human subjects the protection of the rights and

%elfare of all human subjects of scientific e0perimentation7

*he .eclaration of Helsin2i< issued by the &orld "edical +ssociation in 6A@< is the

fundamental document in the field of ethics in biomedical research and has influenced

the formulation of international< regional and national legislation and codes of conduct7*he .eclaration< amended several times< most recently in '((( #+ppendi0 '$< is a

comprehensive international statement of the ethics of research involving human

subjects7 It sets out ethical guidelines for physicians engaged in both clinical and

nonclinical biomedical research7

Since the publication of the CI"S 6AA8 Guidelines< several international

organi!ations have issued ethical guidance on clinical trials7 *his has included< from the

&orld Health rgani!ation< in 6AA< Guidelines for Good #linical Practice for )rials

on Pharmaceutical Products? and from the International Conference on Harmonisation

of *echnical Re4uirements for Registration of Pharmaceuticals for Human /se #ICH$ &

in 6AA@< Guideline on Good #linical Practice< designed to ensure that data generatedfrom clinical trials are mutually acceptable to regulatory authorities in the European

/nion< 9apan and the /nited States of +merica7 *he 9oint /nited )ations Programme

on HI:;+I.S published in '((( the /)+I.S Guidance .ocument Ethical

#onsiderations in HI* Preventive *accine Research7

In '((6 the Council of "inisters of the European /nion adopted a .irective on clinical

trials< %hich %ill be binding in la% in the countries of the /nion from '((7 *he

Council of Europe< %ith more than ( member States< is developing a Protocol on

Biomedical Research< %hich %ill be an additional protocol to the CouncilJs 6AA

Convention on Human Rights and Biomedicine7

)ot specifically concerned %ith biomedical research involving human subjects but

clearly pertinent< as noted above< are international human rights instruments7 *hese are

mainly the /niversal .eclaration of Human Rights< %hich< particularly in its science

provisions< %as highly influenced by the )uremberg Code? the International Covenant

on Civil and Political Rights? and the International Covenant on Economic< Social and

Cultural Rights7 Since the )uremberg e0perience< human rights la% has e0panded to

include the protection of %omen #Convention on the Elimination of +ll =orms of

.iscrimination +gainst &omen$ and children #Convention on the Rights of the Child$7

*hese and other such international instruments endorse in terms of human rights the

general ethical principles that underlie the CI"S International Ethical Guidelines7

GE)ER+- E*HIC+- PRI)CIP-ES

+ll research involving human subjects should be conducted in accordance %ith three

basic ethical principles< namely respect for persons< beneficence and justice7 It is

generally agreed that these principles< %hich in the abstract have e4ual moral force<

guide the conscientious preparation of proposals for scientific studies7 In varying

circumstances they may be e0pressed differently and given different moral %eight< and

their application may lead to different decisions or courses of action7 *he present


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guidelines are directed at the application of these principles to research involving human

subjects7

Respect for persons incorporates at least t%o fundamental ethical considerations<namely1

a$ respect for autonomy< %hich re4uires that those %ho are capable of deliberation about

their personal choices should be treated %ith respect for their capacity for self5

determination? and

b$ protection of persons %ith impaired or diminished autonomy< %hich re4uires that

those %ho are dependent or vulnerable be afforded security against harm or abuse7

Beneficence refers to the ethical obligation to ma0imi!e benefits and to minimi!e

harms7 *his principle gives rise to norms re4uiring that the ris2s of research bereasonable in the light of the e0pected benefits< that the research design be sound< and

that the investigators be competent both to conduct the research and to safeguard the

%elfare of the research subjects7 Beneficence further proscribes the deliberate infliction

of harm on persons? this aspect of beneficence is sometimes e0pressed as a separate

principle< nonmaleficence #do no harm$7

Justice refers to the ethical obligation to treat each person in accordance %ith %hat is

morally right and proper< to give each person %hat is due to him or her7 In the ethics of

research involving human subjects the principle refers primarily to distributive justice,

%hich re4uires the e4uitable distribution of both the burdens and the benefits of

participation in research7 .ifferences in distribution of burdens and benefits are

justifiable only if they are based on morally relevant distinctions bet%een persons? one

such distinction is vulnerability7 D:ulnerabilityD refers to a substantial incapacity to

protect oneKs o%n interests o%ing to such impediments as lac2 of capability to give

informed consent< lac2 of alternative means of obtaining medical care or othere0pensive necessities< or being a junior or subordinate member of a hierarchical group7

+ccordingly< special provision must be made for the protection of the rights and %elfareof vulnerable persons7

Sponsors of research or investigators cannot< in general< be held accountable for unjust

conditions %here the research is conducted< but they must refrain from practices that areli2ely to %orsen unjust conditions or contribute to ne% ine4uities7 )either should they

ta2e advantage of the relative inability of lo%5resource countries or vulnerable

populations to protect their o%n interests< by conducting research ine0pensively and

avoiding comple0 regulatory systems of industriali!ed countries in order to develop

products for the lucrative mar2ets of those countries7

In general< the research project should leave lo%5resource countries or communities

better off than previously or< at least< no %orse off7 It should be responsive to their

health needs and priorities in that any product developed is made reasonably available

to them< and as far as possible leave the population in a better position to obtain

effective health care and protect its o%n health7


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9ustice re4uires also that the research be responsive to the health conditions or needs of

vulnerable subjects7 *he subjects selected should be the least vulnerable necessary to

accomplish the purposes of the research7 Ris2 to vulnerable subjects is most easily

justified %hen it arises from interventions or procedures that hold out for them the

prospect of direct health5related benefit7 Ris2 that does not hold out such prospect must

be justified by the anticipated benefit to the population of %hich the individual researchsubject is representative7

PRE+"B-E

*he term DresearchD refers to a class of activity designed to develop or contribute to

generali!able 2no%ledge7 Generali!able 2no%ledge consists of theories< principles or

relationships< or the accumulation of information on %hich they are based< that can be

corroborated by accepted scientific methods of observation and inference7 In the present

conte0t DresearchD includes both medical and behavioural studies pertaining to humanhealth7 /sually DresearchD is modified by the adjective DbiomedicalD to indicate its

relation to health7

Progress in medical care and disease prevention depends upon an understanding of

physiological and pathological processes or epidemiological findings< and re4uires at

some time research involving human subjects7 *he collection< analysis and

interpretation of information obtained from research involving human beings contribute

significantly to the improvement of human health7

Research involving human subjects includes1

5 studies of a physiological< biochemical or pathological process< or of the response to a

specific intervention %hether physical< chemical or psychological in healthy subjects

or patients?

5 controlled trials of diagnostic< preventive or therapeutic measures in larger groups of

persons< designed to demonstrate a specific generali!able response to these measures

against a bac2ground of individual biological variation?

5 studies designed to determine the conse4uences for individuals and communities of

specific preventive or therapeutic measures? and

5 studies concerning human health5related behaviour in a variety of circumstances and

environments7

Research involving human subjects may employ either observation or physical<

chemical or psychological intervention? it may also either generate records or ma2e use

of e0isting records containing biomedical or other information about individuals %ho

may or may not be identifiable from the records or information7 *he use of such records

and the protection of the confidentiality of data obtained from those records are

discussed in International Guidelines for Ethical Review of Epidemiological Studies

+#I,-S& //0.


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*he research may be concerned %ith the social environment< manipulating

environmental factors in a %ay that could affect incidentally5e0posed individuals7 It is

defined in broad terms in order to embrace field studies of pathogenic organisms and

to0ic chemicals under investigation for health5related purposes7

Biomedical research %ith human subjects is to be distinguished from the practice ofmedicine< public health and other forms of health care< %hich is designed to contribute

directly to the health of individuals or communities7 Prospective subjects may find it

confusing %hen research and practice are to be conducted simultaneously< as %hen

research is designed to obtain ne% information about the efficacy of a drug or other

therapeutic< diagnostic or preventive modality7

+s stated in Paragraph 8' of the .eclaration of Helsin2i< DIn the treatment of a patient<

%here proven prophylactic< diagnostic and therapeutic methods do not e0ist or have

been ineffective< the physician< %ith informed consent from the patient< must be free to

use unproven or ne% prophylactic< diagnostic and therapeutic measures< if in the

physicianKs judgement it offers hope of saving life< re5establishing health or alleviatingsuffering7 &here possible< these measures should be made the object of research<

designed to evaluate their safety and efficacy7 In all cases< ne% information should be

recorded and< %here appropriate< published7 *he other relevant guidelines of this.eclaration should be follo%ed.@

Professionals %hose roles combine investigation and treatment have a special obligation

to protect the rights and %elfare of the patient5subjects7 +n investigator %ho agrees to

act as physician5investigator underta2es some or all of the legal and ethical

responsibilities of the subjectKs primary5care physician7 In such a case< if the subject

%ithdra%s from the research o%ing to complications related to the research or in the

e0ercise of the right to %ithdra% %ithout loss of benefit< the physician has an obligation

to continue to provide medical care< or to see that the subject receives the necessary care

in the health5care system< or to offer assistance in finding another physician7

Research %ith human subjects should be carried out only by< or strictly supervised by<

suitably 4ualified and e0perienced investigators and in accordance %ith a protocol that

clearly states1 the aim of the research? the reasons for proposing that it involve human

subjects? the nature and degree of any 2no%n ris2s to the subjects? the sources from

%hich it is proposed to recruit subjects? and the means proposed for ensuring that

subjectsK consent %ill be ade4uately informed and voluntary7 *he protocol should be

scientifically and ethically appraised by one or more suitably constituted revie% bodies


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Guideline 1: Ethical justification and scientific validity of biomedical research

involving human beings

The ethical justification of biomedical research involving human subjects is the

prospect of discovering new ways of benefiting people's health. uch research can

be ethically justifiable only if it is carried out in ways that respect and protect, andare fair to, the subjects of that research and are morally acceptable within the

communities in which the research is carried out. !oreover, because scientifically

invalid research is unethical in that it e"poses research subjects to ris#s without

possible benefit, investigators and sponsors must ensure that proposed studies

involving human subjects conform to generally accepted scientific principles and

are based on ade$uate #nowledge of the pertinent scientific literature.

#ommentar$ on Guideline

+mong the essential features of ethically justified research involving human subjects ,

including research %ith identifiable human tissue or data


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Ethical revie% committees may function at the institutional< local< regional< or national

level< and in some cases at the international level7 *he regulatory or other governmental

authorities concerned should promote uniform standards across committees %ithin a

country< and< under all systems< sponsors of research and institutions in %hich the

investigators are employed should allocate sufficient resources to the revie% process7

Ethical revie% committees may receive money for the activity of revie%ing protocols< but under no circumstances may payment be offered or accepted for a revie%

committeeLs approval or clearance of a protocol7

Scientific review. +ccording to the .eclaration of Helsin2i # Paragraph $< medical

research involving humans must conform to generally accepted scientific principles< and

be based on a thorough 2no%ledge of the scientific literature< other relevant sources of

information< and ade4uate laboratory and< %here indicated< animal e0perimentation7

Scientific revie% must consider< inter alia< the study design< including the provisions for

avoiding or minimi!ing ris2 and for monitoring safety7 Committees competent to revie%

and approve scientific aspects of research proposals must be multidisciplinary.

Ethical review. *he ethical revie% committee is responsible for safeguarding the rights<

safety< and %ell5being of the research subjects7 Scientific revie% and ethical revie%

cannot be separated1 scientifically unsound research involving humans as subjects is

ipso facto unethical in that it may e0pose them to ris2 or inconvenience to no purpose?

even if there is no ris2 of injury< %asting of subjectsL and researchersL time in

unproductive activities represents loss of a valuable resource7 )ormally< therefore< an

ethical revie% committee considers both the scientific and the ethical aspects of

proposed research7 It must either carry out a proper scientific revie% or verify that a

competent e0pert body has determined that the research is scientifically sound7 +lso< it

considers provisions for monitoring of data and safety7

If the ethical revie% committee finds a research proposal scientifically sound< or verifies

that a competent e0pert body has found it so< it should then consider %hether any

2no%n or possible ris2s to the subjects are justified by the e0pected benefits< direct or

indirect< and %hether the proposed research methods %ill minimi!e harm and ma0imi!e

benefit7 #See Guideline F1 Benefits and ris2s of stud$ participation.0 If the proposal is

sound and the balance of ris2s to anticipated benefits is reasonable< the committee

should then determine %hether the procedures proposed for obtaining informed consent

are satisfactory and those proposed for the selection of subjects are e4uitable7

Ethical review of emergenc$ compassionate use of an investigational therap$. In somecountries< drug regulatory authorities re4uire that the so5called compassionate or

humanitarian use of an investigational treatment be revie%ed by an ethical revie%

committee as though it %ere research7 E0ceptionally< a physician may underta2e the

compassionate use of an investigational therapy before obtaining the approval or

clearance of an ethical revie% committee< provided three criteria are met& a patient

needs emergency treatment< there is some evidence of possible effectiveness of the

investigational treatment< and there is no other treatment available that is 2no%n to be

e4ually effective or superior7 Informed consent should be obtained according to the

legal re4uirements and cultural standards of the community in %hich the intervention is

carried out7 &ithin one %ee2 the physician must report to the ethical revie% committee

the details of the case and the action ta2en< and an independent health5care professionalmust confirm in %riting to the ethical revie% committee the treating physicianKs


15/57

judgment that the use of the investigational intervention %as justified according to the

three specified criteria7 #See also Guideline 68 Commentary section1 ,ther vulnerable

groups.0

%ational +centrali3ed0 or local review. Ethical revie% committees may be created under

the aegis of national or local health administrations< national #or centrali!ed$ medicalresearch councils or other nationally representative bodies7 In a highly centrali!ed

administration a national< or centrali!ed


16/57

Committees that often revie% research proposals directed at specific diseases or

impairments< such as HI:;+I.S or paraplegia< should invite or hear the vie%s of

individuals or bodies representing patients %ith such diseases or impairments7 Similarly<

for research involving such subjects as children< students< elderly persons or employees<

committees should invite or hear the vie%s of their representatives or advocates7

*o maintain the revie% committeeJs independence from the investigators and sponsors

and to avoid conflict of interest< any member %ith a special or particular< direct or

indirect< interest in a proposal should not ta2e part in its assessment if that interest could

subvert the memberLs objective judgment7 "embers of ethical revie% committees

should be held to the same standard of disclosure as scientific and medical research staff

%ith regard to financial or other interests that could be construed as conflicts of interest7

+ practical %ay of avoiding such conflict of interest is for the committee to insist on a

declaration of possible conflict of interest by any of its members7 + member %ho ma2es

such a declaration should then %ithdra%< if to do so is clearly the appropriate action to

ta2e< either at the memberLs o%n discretion or at the re4uest of the other members7

Before %ithdra%ing< the member should be permitted to offer comments on the protocolor to respond to 4uestions of other members7

-ulti4centre research. Some research projects are designed to be conducted in a

number of centres in different communities or countries7 Generally< to ensure that the

results %ill be valid< the study must be conducted in an identical %ay at each centre7

Such studies include clinical trials< research designed for the evaluation of health

service programmes< and various 2inds of epidemiological research7 =or such studies<

local ethical or scientific revie% committees are not normally authori!ed to change

doses of drugs< to change inclusion or e0clusion criteria< or to ma2e other similar

modifications7 *hey should be fully empo%ered to prevent a study that they believe to

be unethical7 "oreover< changes that local revie% committees believe are necessary to

protect the research subjects should be documented and reported to the research

institution or sponsor responsible for the %hole research programme for consideration

and due action< to ensure that all other subjects can be protected and that the research

%ill be valid across sites7

*o ensure the validity of multi5centre research< any change in the protocol should be

made at every collaborating centre or institution< or< failing this< e0plicit inter5centre

comparability procedures must be introduced? changes made at some but not all %ill

defeat the purpose of multi5centre research7 =or some multi5centre studies< scientific and

ethical revie% may be facilitated by agreement among centres to accept the conclusionsof a single revie% committee? its members could include a representative of the ethical

revie% committee at each of the centres at %hich the research is to be conducted< as %ell

as individuals competent to conduct scientific revie%7 In other circumstances< a

centrali!ed revie% may be complemented by local revie% relating to the local

participating investigators and institutions7 *he central committee could revie% the

study from a scientific and ethical standpoint< and the local committees could verify the

practicability of the study in their communities< including the infrastructures< the state of

training< and ethical considerations of local significance7

In a large multi5centre trial< individual investigators %ill not have authority to act

independently< %ith regard to data analysis or to preparation and publication ofmanuscripts< for instance7 Such a trial usually has a set of committees %hich operate


17/57

under the direction of a steering committee and are responsible for such functions and

decisions7 *he function of the ethical revie% committee in such cases is to revie% the

relevant plans %ith the aim of avoiding abuses7

Sanctions. Ethical revie% committees generally have no authority to impose sanctions

on researchers %ho violate ethical standards in the conduct of research involvinghumans7 *hey may< ho%ever< %ithdra% ethical approval of a research project if judged

necessary. *hey should be re4uired to monitor the implementation of an approved

protocol and its progression< and to report to institutional or governmental authorities

any serious or continuing non5compliance %ith ethical standards as they are reflected in

protocols that they have approved or in the conduct of the studies7 =ailure to submit a

protocol to the committee should be considered a clear and serious violation of ethical

standards7

Sanctions imposed by governmental< institutional< professional or other authorities

possessing disciplinary po%er should be employed as a last resort7 Preferred methods of

control include cultivation of an atmosphere of mutual trust< and education and supportto promote in researchers and in sponsors the capacity for ethical conduct of research7

Should sanctions become necessary< they should be directed at the non5compliant

researchers or sponsors7 *hey may include fines or suspension of eligibility to receive

research funding< to use investigational interventions< or to practise medicine7 /nless

there are persuasive reasons to do other%ise< editors should refuse to publish the results

of research conducted unethically< and retract any articles that are subse4uently found to

contain falsified or fabricated data or to have been based on unethical research7 .rug

regulatory authorities should consider refusal to accept unethically obtained data

submitted in support of an application for authori!ation to mar2et a product7 Such

sanctions< ho%ever< may deprive of benefit not only the errant researcher or sponsor but

also that segment of society intended to benefit from the research? such possible

conse4uences merit careful consideration7

Potential conflicts of interest related to project support. Increasingly< biomedical studies

receive funding from commercial firms7 Such sponsors have good reasons to support

research methods that are ethically and scientifically acceptable< but cases have arisen in

%hich the conditions of funding could have introduced bias7 It may happen that

investigators have little or no input into trial design< limited access to the ra% data< or

limited participation in data interpretation< or that the results of a clinical trial may not

be published if they are unfavourable to the sponsorKs product7 *his ris2 of bias may also be associated %ith other sources of support< such as government or foundations7 +s the

persons directly responsible for their %or2< investigators should not enter into

agreements that interfere unduly %ith their access to the data or their ability to analyse

the data independently< to prepare manuscripts< or to publish them7 Investigators must

also disclose potential or apparent conflicts of interest on their part to the ethical revie%

committee or to other institutional committees designed to evaluate and manage such

conflicts7 Ethical revie% committees should therefore ensure that these conditions are

met7 See also -ulti4centre research< above7

Guideline : Ethical review of e!ternally sponsored research


18/57

%n e"ternal sponsoring organiation and individual investigators should submit

the research protocol for ethical and scientific review in the country of the

sponsoring organiation, and the ethical standards applied should be no less

stringent than they would be for research carried out in that country. The health

authorities of the host country, as well as a national or local ethical review

committee, should ensure that the proposed research is responsive to the healthneeds and priorities of the host country and meets the re$uisite ethical standards.

#ommentar$ on Guideline 5

6efinition. *he term e'ternall$ sponsored research refers to research underta2en in a

host country but sponsored< financed< and sometimes %holly or partly carried out by an

e0ternal international or national organi!ation or pharmaceutical company %ith the

collaboration or agreement of the appropriate authorities< institutions and personnel of

the host country7

Ethical and scientific review. Committees in both the country of the sponsor and thehost country have responsibility for conducting both scientific and ethical revie%< as

%ell as the authority to %ithhold approval of research proposals that fail to meet their

scientific or ethical standards7 +s far as possible< there must be assurance that the revie%

is independent and that there is no conflict of interest that might affect the judgement of

members of the revie% committees in relation to any aspect of the research7 &hen the

e0ternal sponsor is an international organi!ation< its revie% of the research protocol

must be in accordance %ith its o%n independent ethical5revie% procedures and

standards7

Committees in the e0ternal sponsoring country or international organi!ation have a

special responsibility to determine %hether the scientific methods are sound and suitable

to the aims of the research? %hether the drugs< vaccines< devices or procedures to be

studied meet ade4uate standards of safety? %hether there is sound justification for

conducting the research in the host country rather than in the country of the e0ternal

sponsor or in another country? and %hether the proposed research is in compliance %ith

the ethical standards of the e0ternal sponsoring country or international organi!ation7

Committees in the host country have a special responsibility to determine %hether the

objectives of the research are responsive to the health needs and priorities of that

country7 *he ability to judge the ethical acceptability of various aspects of a research

proposal re4uires a thorough understanding of a communityKs customs and traditions7*he ethical revie% committee in the host country< therefore< must have as either

members or consultants persons %ith such understanding? it %ill then be in a favourable

position to determine the acceptability of the proposed means of obtaining informed

consent and other%ise respecting the rights of prospective subjects as %ell as of the

means proposed to protect the %elfare of the research subjects7 Such persons should be

able< for e0ample< to indicate suitable members of the community to serve as

intermediaries bet%een investigators and subjects< and to advise on %hether material

benefits or inducements may be regarded as appropriate in the light of a communityKs

gift5e0change and other customs and traditions7

&hen a sponsor or investigator in one country proposes to carry out research in another<the ethical revie% committees in the t%o countries may< by agreement< underta2e to


19/57

revie% different aspects of the research protocol7 In short< in respect of host countries

either %ith developed capacity for independent ethical revie% or in %hich e0ternal

sponsors and investigators are contributing substantially to such capacity< ethical revie%

in the e0ternal< sponsoring country may be limited to ensuring compliance %ith broadly

stated ethical standards7 *he ethical revie% committee in the host country can be

e0pected to have greater competence for revie%ing the detailed plans for compliance< invie% of its better understanding of the cultural and moral values of the population in

%hich it is proposed to conduct the research? it is also li2ely to be in a better position to

monitor compliance in the course of a study7 Ho%ever< in respect of research in host

countries %ith inade4uate capacity for independent ethical revie%< full revie% by the

ethical revie% committee in the e0ternal sponsoring country or international agency is

necessary7

Guideline ": #ndividual informed consent

(or all biomedical research involving humans the investigator must obtain the

voluntary informed consent of the prospective subject or, in the case of an

individual who is not capable of giving informed consent, the permission of a

legally authoried representative in accordance with applicable law. Waiver of

informed consent is to be regarded as uncommon and e"ceptional, and must in all

cases be approved by an ethical review committee.

#ommentar$ on Guideline 7

General considerations. Informed consent is a decision to participate in research< ta2en

by a competent individual %ho has received the necessary information? %ho has

ade4uately understood the information? and %ho< after considering the information< has

arrived at a decision %ithout having been subjected to coercion< undue influence or

inducement< or intimidation7

Informed consent is based on the principle that competent individuals are entitled to

choose freely %hether to participate in research7 Informed consent protects the

individualKs freedom of choice and respects the individualKs autonomy7 +s an additional

safeguard< it must al%ays be complemented by independent ethical revie% of research proposals7 *his safeguard of independent revie% is particularly important as many

individuals are limited in their capacity to give ade4uate informed consent? they include

young children< adults %ith severe mental or behavioural disorders< and persons %ho are

unfamiliar %ith medical concepts and technology #See Guidelines 68


20/57

others7 +de4uate time and resources should be set aside for informed5consent

procedures7

8anguage. Informing the individual subject must not be simply a ritual recitation of the

contents of a %ritten document7 Rather< the investigator must convey the information<

%hether orally or in %riting< in language that suits the individualKs level ofunderstanding7 *he investigator must bear in mind that the prospective subjectLs ability

to understand the information necessary to give informed consent depends on that

individualKs maturity< intelligence< education and belief system7 It depends also on the

investigatorKs ability and %illingness to communicate %ith patience and sensitivity7

#omprehension. *he investigator must then ensure that the prospective subject has

ade4uately understood the information7 *he investigator should give each one full

opportunity to as2 4uestions and should ans%er them honestly< promptly and

completely7 In some instances the investigator may administer an oral or a %ritten test

or other%ise determine %hether the information has been ade4uately understood7

6ocumentation of consent. Consent may be indicated in a number of %ays7 *he subject

may imply consent by voluntary actions< e0press consent orally< or sign a consent form7

+s a general rule< the subject should sign a consent form< or< in the case of

incompetence< a legal guardian or other duly authori!ed representative should do so7

*he ethical revie% committee may approve %aiver of the re4uirement of a signed

consent form if the research carries no more than minimal ris2 that is< ris2 that is no

more li2ely and not greater than that attached to routine medical or psychological

e0amination and if the procedures to be used are only those for %hich signed consent

forms are not customarily re4uired outside the research conte0t7 Such %aivers may also

be approved %hen e0istence of a signed consent form %ould be an unjustified threat to

the subjectKs confidentiality7 In some cases< particularly %hen the information is

complicated< it is advisable to give subjects information sheets to retain? these may

resemble consent forms in all respects e0cept that subjects are not re4uired to sign them7

*heir %ording should be cleared by the ethical revie% committee7 &hen consent has

been obtained orally< investigators are responsible for providing documentation or proof

of consent7

9aiver of the consent re:uirement. Investigators should never initiate research involving

human subjects %ithout obtaining each subjectKs informed consent< unless they have

received e0plicit approval to do so from an ethical revie% committee7 Ho%ever< %hen

the research design involves no more than minimal ris2 and a re4uirement of individualinformed consent %ould ma2e the conduct of the research impracticable #for e0ample<

%here the research involves only e0cerpting data from subjectsK records$< the ethical

revie% committee may %aive some or all of the elements of informed consent7

Renewing consent. &hen material changes occur in the conditions or the procedures of

a study< and also periodically in long5term studies< the investigator should once again

see2 informed consent from the subjects7 =or e0ample< ne% information may have come

to light< either from the study or from other sources< about the ris2s or benefits of

products being tested or about alternatives to them7 Subjects should be given such

information promptly7 In many clinical trials< results are not disclosed to subjects and

investigators until the study is concluded7 *his is ethically acceptable if an ethicalrevie% committee has approved their non5disclosure7


21/57

#ultural considerations7 In some cultures an investigator may enter a community to

conduct research or approach prospective subjects for their individual consent only after

obtaining permission from a community leader< a council of elders< or another

designated authority7 Such customs must be respected7 In no case< ho%ever< may the

permission of a community leader or other authority substitute for individual informed

consent7 In some populations the use of a number of local languages may complicate thecommunication of information to potential subjects and the ability of an investigator to

ensure that they truly understand it7 "any people in all cultures are unfamiliar %ith< or

do not readily understand< scientific concepts such as those of placebo or randomi!ation7

Sponsors and investigators should develop culturally appropriate %ays to communicate

information that is necessary for adherence to the standard re4uired in the informed

consent process7 +lso< they should describe and justify in the research protocol the

procedure they plan to use in communicating information to subjects7 =or collaborative

research in developing countries the research project should< if necessary< include the

provision of resources to ensure that informed consent can indeed be obtained

legitimately %ithin different linguistic and cultural settings7

#onsent to use for research purposes biological materials +including genetic material0

from subjects in clinical trials. Consent forms for the research protocol should include a

separate section for clinical5trial subjects %ho are re4uested to provide their consent for

the use of their biological specimens for research7 Separate consent may be appropriate

in some cases #e7g7< if investigators are re4uesting permission to conduct basic research

%hich is not a necessary part of the clinical trial$< but not in others #e7g7< the clinical trial

re4uires the use of subjectsJ biological materials$7

!se of medical records and biological specimens. "edical records and biological

specimens ta2en in the course of clinical care may be used for research %ithout the

consent of the patients;subjects only if an ethical revie% committee has determined that

the research poses minimal ris2< that the rights or interests of the patients %ill not be

violated< that their privacy and confidentiality or anonymity are assured


22/57

discuss %ith< and< %hen indicated< re4uest the permission of


23/57

6. that subjects have the right of access to their data on demand, even if these

data lac# immediate clinical utility /unless the ethical review committee has

approved temporary or permanent non0disclosure of data, in which case the

subject should be informed of, and given, the reasons for such non0

disclosure1+

7. any foreseeable ris#s, pain or discomfort, or inconvenience to the individual/or others1 associated with participation in the research, including ris#s to

the health or well0being of a subject3s spouse or partner+

*8. the direct benefits, if any, e"pected to result to subjects from participating

in the research

**. the e"pected benefits of the research to the community or to society at large,

or contributions to scientific #nowledge+

*. whether, when and how any products or interventions proven by the

research to be safe and effective will be made available to subjects after they

have completed their participation in the research, and whether they will be

e"pected to pay for them+

*-. any currently available alternative interventions or courses of treatment+*. the provisions that will be made to ensure respect for the privacy of subjects

and for the confidentiality of records in which subjects are identified+

*2. the limits, legal or other, to the investigators' ability to safeguard

confidentiality, and the possible conse$uences of breaches of confidentiality+

*4. policy with regard to the use of results of genetic tests and familial genetic

information, and the precautions in place to prevent disclosure of the results

of a subject's genetic tests to immediate family relatives or to others /e.g.,

insurance companies or employers1 without the consent of the subject+

*5. the sponsors of the research, the institutional affiliation of the investigators,

and the nature and sources of funding for the research+

*6. the possible research uses, direct or secondary, of the subject9s medical

records and of biological specimens ta#en in the course of clinical care /ee

also :uidelines and *6 ;ommentaries1+

*7. whether it is planned that biological specimens collected in the research will

be destroyed at its conclusion, and, if not, details about their storage /where,

how, for how long, and final disposition1 and possible future use, and that

subjects have the right to decide about such future use, to refuse storage,

and to have the material destroyed /ee :uideline ;ommentary1+

8. whether commercial products may be developed from biological specimens,

and whether the participant will receive monetary or other benefits from

the development of such products+*. whether the investigator is serving only as an investigator or as both

investigator and the subject9s physician+

. the e"tent of the investigator's responsibility to provide medical services to

the participant+

-. that treatment will be provided free of charge for specified types of

research0related injury or for complications associated with the research,

the nature and duration of such care, the name of the organiation or

individual that will provide the treatment, and whether there is any

uncertainty regarding funding of such treatment.

. in what way, and by what organiation, the subject or the subject9s family

or dependants will be compensated for disability or death resulting from


24/57

such injury /or, when indicated, that there are no plans to provide such

compensation1+

2. whether or not, in the country in which the prospective subject is invited to

participate in research, the right to compensation is legally guaranteed+

4. that an ethical review committee has approved or cleared the research

protocol.

Guideline &: %btaining informed consent: %bligations of sponsors and investigators

ponsors and investigators have a duty to&

refrain from unjustified deception, undue influence, or intimidation+

see# consent only after ascertaining that the prospective subject has

ade$uate understanding of the relevant facts and of the conse$uences ofparticipation and has had sufficient opportunity to consider whether to

participate+

as a general rule, obtain from each prospective subject a signed form as

evidence of informed consent < investigators should justify any e"ceptions

to this general rule and obtain the approval of the ethical review committee

/ee :uideline ;ommentary, 'ocumentation of consent 1+

renew the informed consent of each subject if there are significant changes

in the conditions or procedures of the research or if new information

becomes available that could affect the willingness of subjects to continue to

participate+ and,

renew the informed consent of each subject in long0term studies at pre0

determined intervals, even if there are no changes in the design or objectives

of the research.

#ommentar$ on Guideline


25/57

2ne% their compliance %as being monitored they might modify their behaviour and

hence invalidate results7 In most such cases< the prospective subjects are as2ed to

consent to remain uninformed of the purpose of some procedures until the research is

completed? after the conclusion of the study they are given the omitted information7 In

other cases< because a re4uest for permission to %ithhold some information %ould

jeopardi!e the validity of the research< subjects are not told that some information has been %ithheld until the research has been completed7 +ny such procedure must receive

the e0plicit approval of the ethical revie% committee7

+ctive deception of subjects is considerably more controversial than simply

%ithholding certain information7 -ying to subjects is a tactic not commonly employed in

biomedical research7 Social and behavioural scientists< ho%ever< sometimes deliberately

misinform subjects to study their attitudes and behaviour7 =or e0ample< scientists have

pretended to be patients to study the behaviour of health5care professionals and patients

in their natural settings7

Some people maintain that active deception is never permissible7 thers %ould permit itin certain circumstances7 .eception is not permissible< ho%ever< in cases in %hich the

deception itself %ould disguise the possibility of the subject being e0posed to more than

minimal ris27 &hen deception is deemed indispensable to the methods of a study the

investigators must demonstrate to an ethical revie% committee that no other research

method %ould suffice? that significant advances could result from the research? and that

nothing has been %ithheld that< if divulged< %ould cause a reasonable person to refuse

to participate7 *he ethical revie% committee should determine the conse4uences for the

subject of being deceived< and %hether and ho% deceived subjects should be informed

of the deception upon completion of the research7 Such informing< commonly called

DdebriefingD< ordinarily entails e0plaining the reasons for the deception7 + subject %ho

disapproves of having been deceived should be offered an opportunity to refuse to allo%

the investigator to use information thus obtained7 Investigators and ethical revie%

committees should be a%are that deceiving research subjects may %rong them as %ell

as harm them? subjects may resent not having been informed %hen they learn that they

have participated in a study under false pretences7 In some studies there may be

justification for deceiving persons other than the subjects by either %ithholding or

disguising elements of information7 Such tactics are often proposed< for e0ample< for

studies of the abuse of spouses or children7 +n ethical revie% committee must revie%

and approve all proposals to deceive persons other than the subjects7 Subjects are

entitled to prompt and honest ans%ers to their 4uestions? the ethical revie% committee

must determine for each study %hether others %ho are to be deceived are similarlyentitled7

Intimidation and undue influence. Intimidation in any form invalidates informed

consent7 Prospective subjects %ho are patients often depend for medical care upon the

physician;investigator< %ho conse4uently has a certain credibility in their eyes< and

%hose influence over them may be considerable< particularly if the study protocol has a

therapeutic component. *hey may fear< for e0ample< that refusal to participate %ould

damage the therapeutic relationship or result in the %ithholding of health services7 *he

physician;investigator must assure them that their decision on %hether to participate

%ill not affect the therapeutic relationship or other benefits to %hich they are entitled7 In

this situation the ethical revie% committee should consider %hether a neutral third partyshould see2 informed consent7


26/57

*he prospective subject must not be e0posed to undue influence7 *he borderline

bet%een justifiable persuasion and undue influence is imprecise< ho%ever7 *he

researcher should give no unjustifiable assurances about the benefits< ris2s or

inconveniences of the research< for e0ample< or induce a close relative or a community

leader to influence a prospective subjectKs decision7 #See also Guideline 1 Individual

informed consent.0

Ris2s. Investigators should be completely objective in discussing the details of the

e0perimental intervention< the pain and discomfort that it may entail< and 2no%n ris2s

and possible ha!ards7 In comple0 research projects it may be neither feasible nor

desirable to inform prospective participants fully about every possible ris27 *hey must<

ho%ever< be informed of all ris2s that a reasonable personJ %ould consider material to

ma2ing a decision about %hether to participate< including ris2s to a spouse or partner

associated %ith trials of< for e0ample< psychotropic or genital5tract medicaments7 #See

also Guideline F Commentary


27/57

consent7 If by that time the researcher has not obtained either consent or permission

o%ing either to a failure to contact a representative or to a refusal of either the patient or

the person or body authori!ed to give permission the participation of the patient as a

subject must be discontinued7 *he patient or the person or body providing authori!ation

should be offered an opportunity to forbid the use of data derived from participation of

the patient as a subject %ithout consent or permission7

&here appropriate< plans to conduct emergency research %ithout prior consent of the

subjects should be publici!ed %ithin the community in %hich it %ill be carried out7 In

the design and conduct of the research< the ethical revie% committee< the investigators

and the sponsors should be responsive to the concerns of the community7 If there is

cause for concern about the acceptability of the research in the community< there should

be a formal consultation %ith representatives designated by the community7 *he

research should not be carried out if it does not have substantial support in the

community concerned7 #See Guideline F Commentary


28/57

"cceptable recompense. Research subjects may be reimbursed for their transport and

other e0penses< including lost earnings< associated %ith their participation in research7

*hose %ho receive no direct benefit from the research may also receive a small sum of

money for inconvenience due to their participation in the research7 +ll subjects may

receive medical services unrelated to the research and have procedures and tests

performed free of charge7

!nacceptable recompense. Payments in money or in 2ind to research subjects should

not be so large as to persuade them to ta2e undue ris2s or volunteer against their better

judgment7 Payments or re%ards that undermine a personKs capacity to e0ercise free

choice invalidate consent7 It may be difficult to distinguish bet%een suitable

recompense and undue influence to participate in research7 +n unemployed person or a

student may vie% promised recompense differently from an employed person7 Someone

%ithout access to medical care may or may not be unduly influenced to participate in

research simply to receive such care7 + prospective subject may be induced to

participate in order to obtain a better diagnosis or access to a drug not other%ise

available? local ethical revie% committees may find such inducements acceptable7 "onetary and in52ind recompense must< therefore< be evaluated in the light of the

traditions of the particular culture and population in %hich they are offered< to

determine %hether they constitute undue influence7 *he ethical revie% committee %ill

ordinarily be the best judge of %hat constitutes reasonable material recompense in

particular circumstances7 &hen research interventions or procedures that do not hold

out the prospect of direct benefit present more than minimal ris2< all parties involved in

the research sponsors< investigators and ethical revie% committees in both funding

and host countries should be careful to avoid undue material inducement7

Incompetent persons. Incompetent persons may be vulnerable to e0ploitation for

financial gain by guardians7 + guardian as2ed to give permission on behalf of an

incompetent person should be offered no recompense other than a refund of travel and

related e0penses7

9ithdrawal from a stud$. + subject %ho %ithdra%s from research for reasons related to

the study< such as unacceptable side5effects of a study drug< or %ho is %ithdra%n on

health grounds< should be paid or recompensed as if full participation had ta2en place7 +

subject %ho %ithdra%s for any other reason should be paid in proportion to the amount

of participation7 +n investigator %ho must remove a subject from the study for %ilful

noncompliance is entitled to %ithhold part or all of the payment7

Guideline ): Benefits and ris*s of study participation

(or all biomedical research involving human subjects, the investigator must ensure

that potential benefits and ris#s are reasonably balanced and ris#s are minimied.

Interventions or procedures that hold out the prospect of direct diagnostic,

therapeutic or preventive benefit for the individual subject must be justifiedby the e"pectation that they will be at least as advantageous to the


29/57

individual subject, in the light of foreseeable ris#s and benefits, as any

available alternative. >is#s of such 'beneficial' interventions or procedures

must be justified in relation to e"pected benefits to the individual subject.

>is#s of interventions that do not hold out the prospect of direct diagnostic,

therapeutic or preventive benefit for the individual must be justified inrelation to the e"pected benefits to society /generaliable #nowledge1. The

ris#s presented by such interventions must be reasonable in relation to the

importance of the #nowledge to be gained.

#ommentar$ on Guideline >

*he .eclaration of Helsin2i in several paragraphs deals %ith the %ell5being of research

subjects and the avoidance of ris27 *hus< considerations related to the %ell5being of the

human subject should ta2e precedence over the interests of science and society

+Paragraph ?$? clinical testing must be preceded by ade4uate laboratory or animal

e0perimentation to demonstrate a reasonable probability of success %ithout undue ris2# Paragraph $? every project should be preceded by careful assessment of predictable

ris2s and burdens in comparison %ith foreseeable benefits to the subject or to others

# Paragraph $7

Biomedical research often employs a variety of interventions of %hich some hold out

the prospect of direct therapeutic benefit #beneficial interventions$ and others are

administered solely to ans%er the research 4uestion #non5beneficial interventions$7

Beneficial interventions are justified as they are in medical practice by the e0pectationthat they %ill be at least as advantageous to the individuals concerned< in the light of

both ris2s and benefits< as any available alternative7 )on5beneficial interventions are

assessed differently? they may be justified only by appeal to the 2no%ledge to be

gained7 In assessing the ris2s and benefits that a protocol presents to a population< it is

appropriate to consider the harm that could result from forgoing the research7

Paragraphs and 6F of the .eclaration of Helsin2i do not preclude %ell5informed

volunteers< capable of fully appreciating ris2s and benefits of an investigation< from

participating in research for altruistic reasons or for modest remuneration7

-inimi3ing ris2 associated with participation in a randomi3ed controlled trial. In

randomi!ed controlled trials subjects ris2 being allocated to receive the treatment that

proves inferior7 *hey are allocated by chance to one of t%o or more intervention arms

and follo%ed to a predetermined end5point7 #Interventions are understood to include

ne% or established therapies< diagnostic tests and preventive measures7$ +n intervention

is evaluated by comparing it %ith another intervention #a control$< %hich is ordinarily

the best current method< selected from the safe and effective treatments available

globally


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for purposes of conducting the trial< %ithhold therapy that is 2no%n to be superior to the

intervention being tested< unless the %ithholding can be justified by the standards set

forth in Guideline 667 +lso< the investigator must provide in the research protocol for

the monitoring of research data by an independent board #.ata and Safety "onitoring

Board$? one function of such a board is to protect the research subjects from previously

un2no%n adverse reactions or unnecessarily prolonged e0posure to an inferior therapy7 )ormally at the outset of a randomi!ed controlled trial< criteria are established for its

premature termination #stopping rules or guidelines$7

Ris2s to groups of persons7 Research in certain fields< such as epidemiology< genetics or

sociology


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&hen the ris2s of such interventions do not e0ceed those associated %ith routine

medical or psychological e0amination of such persons< there is no re4uirement for

special substantive or procedural protective measures apart from those generally

re4uired for all research involving members of the particular class of persons7 &hen the

ris2s are in e0cess of those< the ethical revie% committee must find1 6$ that the research

is designed to be responsive to the disease affecting the prospective subjects or toconditions to %hich they are particularly susceptible? '$ that the ris2s of the research

interventions are only slightly greater than those associated %ith routine medical or

psychological e0amination of such persons for the condition or set of clinical

circumstances under investigation? 8$ that the objective of the research is sufficiently

important to justify e0posure of the subjects to the increased ris2? and $ that the

interventions are reasonably commensurate %ith the clinical interventions that the

subjects have e0perienced or may be e0pected to e0perience in relation to the condition

under investigation7

If such research subjects< including children< become capable of giving independent

informed consent during the research< their consent to continued participation should beobtained7

*here is no internationally agreed< precise definition of a Dslight or minor increaseD

above the ris2s associated %ith routine medical or psychological e0amination of such

persons7 Its meaning is inferred from %hat various ethical revie% committees have

reported as having met the standard7 E0amples include additional lumbar punctures or

bone5marro% aspirations in children %ith conditions for %hich such e0aminations are

regularly indicated in clinical practice7 *he re4uirement that the objective of the

research be relevant to the disease or condition affecting the prospective subjects rules

out the use of such interventions in healthy children7

*he re4uirement that the research interventions be reasonably commensurate %ith

clinical interventions that subjects may have e0perienced or are li2ely to e0perience for

the condition under investigation is intended to enable them to dra% on personal

e0perience as they decide %hether to accept or reject additional procedures for research

purposes7 *heir choices %ill< therefore< be more informed even though they may not

fully meet the standard of informed consent7

#See also Guidelines 1 Individual informed consent ? 681 Research involving vulnerable

persons; 61 Research involving children; and 61 Research involving individuals who

b$ reason of mental or behavioural disorders are not capable of giving ade:uatel$informed consent.0

Guideline 1-: Research in populations and communities with limited resources

)efore underta#ing research in a population or community with limited resources,

the sponsor and the investigator must ma#e every effort to ensure that&


32/57

the research is responsive to the health needs and the priorities of the

population or community in which it is to be carried out+ and

any intervention or product developed, or #nowledge generated, will be

made reasonably available for the benefit of that population or community.

#ommentar$ on Guideline @

*his guideline is concerned %ith countries or communities in %hich resources are

limited to the e0tent that they are< or may be< vulnerable to e0ploitation by sponsors and

investigators from the relatively %ealthy countries and communities7

Responsiveness of research to health needs and priorities7 *he ethical re4uirement that

research be responsive to the health needs of the population or community in %hich it is

carried out calls for decisions on %hat is needed to fulfil the re4uirement . It is not

sufficient simply to determine that a disease is prevalent in the population and that ne%

or further research is needed1 the ethical re4uirement of DresponsivenessD can befulfilled only if successful interventions or other 2inds of health benefit are made

available to the population7 *his is applicable especially to research conducted in

countries %here governments lac2 the resources to ma2e such products or benefits

%idely available7 Even %hen a product to be tested in a particular country is much

cheaper than the standard treatment in some other countries< the government or

individuals in that country may still be unable to afford it7 If the 2no%ledge gained from

the research in such a country is used primarily for the benefit of populations that can

afford the tested product< the research may rightly be characteri!ed as e0ploitative and<

therefore< unethical.

&hen an investigational intervention has important potential for health care in the hostcountry< the negotiation that the sponsor should underta2e to determine the practical

implications of DresponsivenessD< as %ell as Dreasonable availabilityD< should include

representatives of sta2eholders in the host country? these include the national

government< the health ministry< local health authorities< and concerned scientific and

ethics groups< as %ell as representatives of the communities from %hich subjects are

dra%n and non5governmental organi!ations such as health advocacy groups7 *he

negotiation should cover the health5care infrastructure re4uired for safe and rational use

of the intervention< the li2elihood of authori!ation for distribution< and decisions

regarding payments< royalties< subsidies< technology and intellectual property< as %ell as

distribution costs< %hen this economic information is not proprietary7 In some cases<

satisfactory discussion of the availability and distribution of successful products %ill

necessarily engage international organi!ations< donor governments and bilateral

agencies< international nongovernmental organi!ations< and the private sector7 *he

development of a health5care infrastructure should be facilitated at the onset so that it

can be of use during and beyond the conduct of the research7

+dditionally< if an investigational drug has been sho%n to be beneficial< the sponsor

should continue to provide it to the subjects after the conclusion of the study< and

pending its approval by a drug regulatory authority7 *he sponsor is unli2ely to be in a

position to ma2e a beneficial investigational intervention generally available to the

community or population until some time after the conclusion of the study< as it may be


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in short supply and in any case cannot be made generally available before a drug

regulatory authority has approved it7

=or minor research studies and %hen the outcome is scientific 2no%ledge rather than a

commercial product< such comple0 planning or negotiation is rarely< if ever< needed7

*here must be assurance< ho%ever< that the scientific 2no%ledge developed %ill be usedfor the benefit of the population7

Reasonable availabilit$7 *he issue of Dreasonable availabilityD is comple0 and %ill need

to be determined on a case5by5case basis7 Relevant considerations include the length of

time for %hich the intervention or product developed< or other agreed benefit< %ill be

made

Documents

CIOMS International Ethical Guidelines for Biomedical Resear