ethical clinical research
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Urmila Thatte
Seth GS Medical College
Ethical Clinical Research
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ETHICS
Moral code of conduct defining the right and
wrong behavior in a civil society and comes from
within.
It is different from Law which regulates external
behavior.
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What is Clinical Research?
A systematic investigation in human beings
designed to produce generalisable knowledge
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Practice vs. Research
Prac
tice:
Interventions thatare designed solely
to enhance thewell-being of anindividual patientthat has a
reasonableexpectation ofsuccess
Resea
rch:
Activity designedto test an
hypothesis, permitconclusions to bedrawn; andthereby develop or
contribute togeneralizableknowledge
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Patients vs. Participant
Therapeutic misconception
Vulnerability of the patient
Doctor-patient vs. Investigator-participantrelationship and heirarchy
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Ethics in Biomedical Research
Right of thehumanparticipant
tounderstand
the nature of research,
risks & benefitsinvolved
to agree or not agree
to participate.
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14th May 1796
Jenner approached a farmer called Phipps
Asked if he could inoculate his son James against smallpox
Explained that if his theory was correct, James would never contract smallpox.
Surprisingly, the farmer agreed.
Jenner made two small cuts on James's left arm. He then poured the liquid from amilkmaids cowpox sores into the open wounds
James went down with cowpox but was not very ill.
Six weeks later when James had recovered, Jenner vaccinated him again, this time withthe smallpox virus.
To Jenner's relief James did not catch smallpox. His experiment had worked.
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1900
United States Army Yellow Fever Commission: how doesyellow fever get transmitted (Walter Reed) conducted in
experimental stations just outside Havana
Paid $100 in US gold to participants to allow themselvesto be bitten by infected mosquitoes (yellow fever)
Additional $100 if they consequently contracted the viraldisease
Payable to family in case of death
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Medical science must advance, but individual physician has special
duty and major responsibility for life and health of patient-subject
Risks proportionate to anticipated benefits
Tested in advance on animals Unambiguous consent Special caution if minors
Exploitation of social hardship is unethical
Academic training should stress special obligations when conducting
research or publishing
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Regulations on New Therapy and HumanExperimentation from the Reich Minister of the
Interior, Feb 1931
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End point of experiments - DEATH
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Defendants and Defense Counsel15 of 23 guilty, 7 hanged, 5 life sentences
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Nuremberg Code 1949: 10 points
voluntary (informed) consent must be obtained:investigators responsibility
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Clinical Trial Ethics: Nuremberg CodeThe code
specifies that:
volunteers have the
right to withdrawat any time
experiments mustprovide benefits
for society
avoid unnecessaryinjury
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Thalidomide Trial
Thalidomide was approved as a sedative
No danger to mother but extremely damagingto the foetus
Drug given to cure morning sickness
Subjects were not informed of experimental
drugs
Subjects were not asked to give their consent
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Harris-Kefauver Amendment to Food,Drugs and Cosmetics Act, 1962
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Declaration of Helsinki: 1964
Adopted by the 18th World Medical Assembly
Revised 6 times
Latest version 2008, Seoul, South Korea
Para 13: protocols must be submitted to an Ethics Committee for
review, which must be independent of the investigator, the sponsor
or any other kind of undue influence.
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Tuskegee Syphilis Study
American medical research
project conducted by the
U.S. Public Health Servicefrom 1932 to 1972,
Examined the natural course
of untreated syphilis in black
American men.
Taliaferro Clark,Head of the
Public HealthService at thebeginning of theTuskegeeExperiment
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Tuskegee SyphilisStudy
Results:
28 deaths,
100 cases of disability,
19 cases of congenital
syphilisLack of informed consent, putting subjects and their
families to risk, exploitation of vulnerable population,
deception, withholding information, no benefit to subjects
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UGCertificate
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Tuskegee 1997
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The Belmont Report
Ethical Principles and Guidelines for the Protection ofHuman Subjects of Research
The National Commission for the Protection of Human Subjects of Biomedicaland Behavioral ResearchApril 18, 1979
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The Belmont Report: 3 principles
Respect forPersons-
autonomy of
individuals
Special protectionfor those with
diminished
autonomy
Beneficence
maximize the
possible benefits
minimize possible
harm
Justice
subjects should be
selected fairly to
ensure that the
benefits and
burdens of medicalresearch are
evenly distributed
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ICH - International Conference onHarmonization, 1996
Joint initiative by regulators and
industry from three regions - US, EU &
Japan
Three observers:
WHO
Canada
IFPMA (International Federation of
Pharmaceutical Manufacturers
Association)
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GCP = Good Clinical Research Practice
A standard for the
design,
conduct,
monitoring,
recording,
auditing,
reporting
of clinical trials
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International
Scientific &Ethical quality
Standard
DESIGN
COLLECT
Patient Safety Credibility of Data
Good Clinical Practice
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India
2001 Indian GCP
2005 Schedule Y of Drugs and
Cosmetics Act Amendment:pertinent to clinical trials
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ICMR Guidelines
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An erosion ofpublic trust...
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Informed Consentndependent Review11/14/201027 UG Certificate Course
Twin pillars of human
protection
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Informed consent
A process by which a participant voluntarily confirms his or her
willingness to participate in a particular trial, after having been
informed of all aspects of the trial that are relevant to the participants
decision to participate.
Informed consent is documented by means of a written, signed and
dated informed consent form.
ICH- GCP 1.28
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Part I : ParticipantInformation Sheet
(PIS)
Provides informationabout the study.
Part II : Consent form
Consent documented
Both integrated in toone document called
the Informed Consent
Document (ICD)
Informed Consent Document
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Informed consent
Consent given by a competent individual who
Has received the necessary information
Has understood the information
And having understood the information has arrived
at a decision without having been under any
coercion, undue influence or inducement or
intimidation
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Informed consent
Written informed consent
Voluntary
from every subject
before any study related procedure
and documented on EC approved form
Signed copy given to participant
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Who gives the consent?
Participant
if subject unable to giveconsent (minor, dementia
etc.) then -
Legally
acceptablerepresentative
(LAR)
subject should be informed
to the extent compatiblewith his/herunderstanding and consentsought and documented.
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How should the consent be documented?
Signed anddated by
Subject / subjectslegally acceptable
representative
Person conductingthe informed
consent discussionIf illiterate, an
impartial witness
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Informed Consent: Non-English speaking
Summaryand
consent inthe
vernacular
Written
translation
Thumbimpressions
allowedWitness
Documentmethod in
source
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Informed Consent: Children
Approval of older children:understand the concepts: assent
Consent from parents/legallyacceptable representative
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. . . is not a piece of paper.
. . . is not a signature.
It is a PROCESS by which we . . .. . . ENSURE that our subjects right to be informed, and right to consent to
research, is protected.
. . . DOCUMENT our efforts to protect the subjects rights to the satisfaction ofindependent observers.
Informed Consent . . .
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Informed ConsentIndependentReview
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Twin pillars of human
protection
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Ethics Committee
review,
approve the initiation ofand
conduct periodic review
of biomedical researchinvolving human subjects.
Any board,committee
or othergroup
formally
designatedby aninstitution to
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All proposals onbiomedical research
involving humansubjects must be
cleared by an
Ethics Committee
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An objectivereview of researchactivities involving
human subjects
by a group ofdiverse
individuals is
most likely toprotect human
subjects and
promote ethicallysound research
Ethics Committees: Why?
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Composition of the EC
A reasonable
number of
members who
collectively have
the
qualifications and
experience
the science,
medical aspects
and
ethics of the
proposed trial
to review and
evaluate
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What does an EC do for Clinical Research?
Before thestudy begins:
Review andapproval of
research proposal
Decision makingprocess
Record keeping
During thestudy:
Review ofamendments
(Protocol, ICD)
Review of
Serious AdverseEvents
Protocoldeviations
Monitoringprogress
(reports, on-site)
Record keeping
After thestudy:
Study report,
Post trialmanagement
Publishing
Record keeping
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Criteria For Approval
Suitability ofInvestigator,Protocol and
informed consentprocesses
EquitableSelection Of
Subjects
Time Provision Confidentiality ofsubjects and data
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No study can be started without EC approval
No changes made without prior written ECapproval
EC may revoke any prior approval dependingon ongoing review
EC : Approval
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Challenges
If studies areNOT submittedfor review, thenthe safeguard of
ECs ismeaningless!
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14 November 2010Pharmatech 20084
The Road Not TakenRobert Frost
Two roads diverged in a yellow wood, I could not travel both
. long I stood
I shall be telling this with a sighSomewhere ages and ages hence:
Two roads diverged in a wood, and I,I took the one less traveled,And that has made all the difference.