The adequacy of the ethics review process in - UCL Discovery

257 Pages·2011·1.31 MB·English

by  Kaur, S.

THE ADEQUACY OF THE ETHICS REVIEW
PROCESS IN MALAYSIA: PROTECTION OF THE
INTERESTS OF MENTALLY INCAPACITATED
ADULTS WHO ENROL IN CLINICAL TRIALS.
SHARONKAUR
UNIVERSITYCOLLEGELONDON(UCL)
THESIS SUBMITTEDINFULFILMENT
OFTHEREQUIREMENTS FOR
THE DEGREEOF DOCTOROFPHILOSOPHY
1
I, Sharon Kaur, confirm that the work presented in this thesis is my
own. Where informationhas been derivedfromothersources,I confirm
thatthishasbeenindicatedinthethesis.
………………………………
SharonKaur
2
ABSTRACT
The objective of this thesis is to answer the question, “does the ethics
committee reviewprocess inMalaysia provide meaningful protectionto
mentallyincapacitatedadultswhoenrol inclinicalresearchtrials?”
This question is answered by examining three important aspects of the
ethics review process. First, the quality of the deliberations of ethics
committees is examined by looking at the underlying principles that
are meant to guide ethics decision-making. Second, the thesis looks at
the current regulatory framework under which ethics committees
operate and considers the adequacy of these guidelines in protecting
human subjects. Finally, this thesis considers the notion of conflicts of
interests in the clinical trials arena and calls into question the
independence of the ethics review process and how this impacts on the
interests of human subjects in general and mentally incapacitated
adultsinparticular.
The conclusion reached at the end of this thesis is that the ethics
review process in Malaysia fails adequately to provide meaningful
protection to mentally incapacitated adults. While the reasons for this
are many, several factors are particularly significant, namely, the
creation of a globalised clinical trials market, the lack of formal and
systematic training of ethics committee members and the institutional
structuresofethicscommittees.
Although the main focus of this thesis is the Malaysian ethics review
process, many of the comments and discussions put forward in this
thesis are highly relevant to the ethics review processes in other
jurisdictions given the international regulatory scheme that currently
governstheconductofclinicaltrialsinmanypartsoftheworld.
3
ACKNOWLEDGEMENTS
In thinking about and writing this thesis, I have received advice and
assistance from a number of people, all of whom I gratefully thank. I
am deeply indebted to my principal supervisor, Professor Michael
Freeman, for his invaluable guidance. I have benefited tremendously
from his intellectual stimulation, advice and support, especially during
periods of self-doubt over the years. I am also very grateful to him for
reading through the final draft of this thesis with great care. I am
particularly grateful to my secondary supervisor, Professor Dame
Hazel Genn, for her critical comments and guidance. I am also grateful
to Professor Stephen Guest for providing me with supervision for the
firstyearofmyresearch.
I must acknowledge my profound gratitude to my sister, Karen, who
not only provided me with strong support and encouragement, but also
contributed her valuable time to read through the entire thesis and
provide helpful comments. Thanks are also due to my colleagues, Dr
Tay Pek San and Dr Azmi Sharom who proofread some chapters of the
thesisaswell.
On a personal note, I must thank my father, Dato’ Dr Gurmukh Singh,
for his support and encouragement. I will also always be grateful for
the friendship and the intellectual stimulation provided by my
coursemates on the PhD programme at UCL, as well as the unending
supportoffriendsatAllSoulsChurch,London.
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TABLEOFCONTENTS
ABSTRACT...............................................................................................3
ACKNOWLEDGEMENTS........................................................................4
1 ChapterOne........................................................................................8
Introduction...............................................................................................8
1.1 ClinicalTrials................................................................................8
1.1.1 EvolutionofClinicalTrials....................................................9
1.1.2 Clinical trials–humansubjectprotection..........................16
1.2 MentallyIncapacitatedPatients.................................................17
1.2.1 Vulnerablepopulations........................................................17
1.2.2 Mentallyincapacitatedpatientsandclinicaltrials............21
1.3 Objective,scope,outlineofchapter,terminologyandresearch
methodology.........................................................................................23
1.3.1 Objectiveoftheresearch......................................................23
1.3.2 Scopeofthestudyandoutlineofthechapters...................24
1.3.3 ResearchMethodology.........................................................27
2 Chapter2...........................................................................................32
TheMalaysianContext...........................................................................32
2.1 MedicalResearchinMalaysia–ABriefHistory........................32
2.1.1 Early days.............................................................................32
2.1.2 Emergenceofthelocalclinicaltrialindustry.....................34
2.1.3 Governmentsupportofclinicaltrialindustry....................38
2.1.4 Globalisationandtheimpactonhumansubjectprotection
40
2.2 RegulationofclinicaltrialsinMalaysia....................................42
2.2.1 Legislation............................................................................42
2.2.2 Guidelines.............................................................................43
2.3 IncapacitatedsubjectsandclinicaltrialsinMalaysia..............46
2.3.1 Legislation............................................................................46
2.3.2 Guidelines.............................................................................55
2.4 Ethicscommitteereview..............................................................56
2.4.1 Historyofethicsreview........................................................57
5
2.4.2 U.S.Experience....................................................................58
2.4.3 EthicsReviewinMalaysia...................................................63
3 Chapter3...........................................................................................67
Ethics committeereviewandtheethicsofclinicalresearch................67
3.1 Historyofclinicalresearchmisconduct......................................70
3.1.1 WorldWarIIHumanExperimentsandtheNuremberg
Code 70
3.1.2 Henry Beecher’sArticleandtheDeclarationofHelsinki...77
3.1.3 TheTuskegeeSyphilisStudyandtheBelmontReport......83
3.2 Basisofresearchmisconduct-UndervaluationofHumanLife88
3.2.1 Groupbasedundervaluationofhumanlife.........................89
3.2.2 Undervaluationoftheindividualperson............................91
3.3 EthicalBasis forClinicalResearchInvolvingHumanSubjects98
3.3.1 Howtovaluehumanlife?.....................................................99
3.3.2 Valuing lifebasedonhumandignity.................................101
3.3.3 HumanDignityasaccordedtoallhumans.......................104
4 Chapter4.........................................................................................118
Ethics Committee ReviewandtheICH-GCPGuideline.....................118
4.1 Ethicscommittees’rolesandresponsibilitiesandICH-GCP...120
4.1.1 Safeguardingrightssafety andwell-beingofall trial
subjects –substantiveduties.........................................................120
4.1.2 Administrativeduties........................................................125
5 Chapter5.........................................................................................157
Ethics Committee ReviewandConflictsofInterest............................157
5.1 Historicalcontextofindependentethicsreview........................157
5.2 ConflictsofInterest....................................................................160
5.2.1 HistoryofConflictsofInterestintheResearch
Environment..................................................................................160
5.2.2 CurrentEmphasis–financialconflictsofinterest...........162
5.3 WhatareConflictsofInterest?..................................................165
5.4 ConflictsofInterestasthe ClashBetweenPrimaryand
SecondaryInterests............................................................................166
6
5.4.1 (1)Whatsortsofrelationshipsgiverisetoprimary
interests?–Erde’ssocialrole........................................................167
5.4.2 Whichrelationshipsintheresearchenvironmentfulfil
Erde’ssocialrole?...........................................................................169
5.4.3 (2)Howareprimaryintereststobediscovered?...............185
5.4.4 (3)Whencanitbesaidthatinterestsotherthanprimary
interestsamounttosecondaryinterests?.....................................204
5.4.5 SecondaryInterestsandResearchEthicsCommittees....220
6 Chapter6.........................................................................................232
Conclusion.............................................................................................232
6.1 Areethicscommitteesindependent?..........................................234
6.2 Doethicscommittees engageinmeaningfulethicaldiscourse?235
6.3 Conclusion.................................................................................239
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1 ChapterOne
Introduction
The objective of this research is to analyse and evaluate the adequacy
oftheethicsreviewprocessinproviding an adequatelevel ofprotection
to mentally incapacitated adults who participate in clinical trials in
Malaysia.
Clinical Trials
Advances in medical science are largely achieved by way of medical
research projects. To highlight a few examples, there would be no
organ transplants, vaccinations or chemotherapy drugs if it were not
for research. Medical research covers a broad range of activities aimed
at improving or maintaining human health. Research activities range
from basic research in areas such as animal studies, psychology,
statistics, economics, physics, chemistry,etc; to clinical research, which
involvesresearchonhumanparticipants.1
The clinical research trial is medical research that is carried out on
human participants and is the last leg of along journey. The American
National Institutes of Health defines a clinical research trial2 as a
prospective biomedical or behavioural research study of human
subjects that is designed to answer specific questions about biomedical
or behavioural interventions (drugs, treatments, devices, or new ways
ofusing knowndrugs,treatments,ordevices).
Clinicalresearchtrialscanbedescribedinseveralways.They maybe
1 See the U.K. Medical Research Council description of clinical trials at
http://www.mrc.ac.uk/Achievementsimpact/Clinicaltrials/Whatareclinicaltrials/index.htm
accessedAugust17,2010
2Athttp://clinicaltrials.gov/ct2/info/glossaryaccessedonAugust17,2010
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described as being therapeutic or non-therapeutic in nature.3
Therapeutic trials are run on subjects with not only a viewof proving a
particular hypothesis, but also of providing a curative therapy for a
particular condition. To this end, all research participants are
necessarily patients suffering from the particular illness, condition or
disability being studied. A therapeutic clinical trial is carried out at a
point at which a drug or therapy has shown enough promise and is
deemed sufficiently safe to be tested on human subjects. It is usually
the last step before a drug or therapy is introduced to the general
population. Non-therapeutic trials on the other hand, are usually run
to test the safety profiles of drugs or are bio-equivalency studies and
trial subjects are usually healthy volunteers.4 Clinical research trials
may also be described according to the objects being studied. They may
involve testing drugs, diagnostic methods, devices or even treatment
methodsandmay beinvasiveornon-invasive.
In order fully to appreciate the context in which modern clinical trials
are run and the reasons for the development of principles and
mechanisms to protect human subjects, it is necessary to first consider
howclinicalresearchhasevolvedoverthecenturies.
EvolutionofClinicalTrials
The modern scientific tradition of medicine5 has evolved over centuries
of trial and error. Early physicians worked at the bedside and
hypothesisedcauses andeffectsofdiseases andillnessesandtestedout
their theories on their patients. Treatment modalities were more often
3Theuseoftheterminologytherapeutictrialinsteadofnontherapeutictrialhasbeenthesubject
of some debate as using the word therapeutic seems to infer that the primary aim of the trial is
treatment,whichis notthecaseastheprimaryaimofanytrialisthegenerationofgeneralisable
knowledge.SeeJ.MenikoffandE.P.Richards,Whatthedoctordidn'tsay:thehiddentruthabout
medicalresearch,(NewYork;Oxford2006)at22
4 The subject population may also include patients who are not suffering from the specific
conditionthatisbeingresearched.
5Hippocratesand hisfollowersaregenerallyrecognisedashaving laiddown thefoundationsfor the
modernscientifictraditionofmedicine.
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than not based on anecdotal evidence of past successes or failures to
cure patients. In this way the breadth and depth of medical knowledge
grewslowlyandfitfully.Thelinebetweenmedicalpracticeandmedical
research had yet to be drawn and in truth, almost all medical practice
was also clinical research. Bedside medicine6 as practised by the
Hippocratics, was founded on the idea of humoral medicine, which
emphasised the importance of diet, exercise and bathing and believed
in the body’s ability to heal itself. This form of medicine was typically
observationalratherthanexperimental.7
Over time, medical practice moved8 from the bedside into the hospital
andthe science of medicine movedfrom passive observationof patients
to active laboratory based medicine. The emergence of hospital
medicine transformed the practice of medicine in both terms oflocation
and its content. The hospital became the centre of medical teaching,
research and the arbiter of medical knowledge.9 This type of medicine
was especially associated with the city of Paris between 1794 and
1848.10
Clinical research began to take on a more systematic and scientific
approach during the ascendency of hospital medicine since it was in
the hospitals where the “three pillars of the new medicine – physical
6 Bedside medicine is said to have held sway in Western Europe from the Middle Ages to the 18th
Century. See Andrew Cunningham and Perry Williams, The Laboratory Revolution in Medicine
(Cambridge:CambridgeUniversityPress,1992).at1
7 Fewrecordsexistof pureresearchactivitiesandthemostfrequentlycitedcasesinvolvetestingthe
efficacyofpoisonsoncondemnedprisoners.(SeeSPost(ed)EncyclopaediaofBioethics3rdEd,Vol4,
ThomsonGale,pg2316)Someaccountsofhumanvivisectionalexperimentswerealsorecordedinthis
ageandineachcasecondemnedcriminalswerealsousedassubjects.(S.F.Spicker,TheUseofhuman
beingsinresearch:withspecialreferencetoclinicaltrials,(Dordrecht;London1988)at33)
8 The history of Western medicinehas been described as involving fivetypes of medicine: bedside:
medicine, librarymedicine,hospitalmedicine, communitymedicineandlaboratorymedicine.SeeW.
Byrnum,“ReflectionsontheHistoryofHumanExperimentation”inSpicker,S.F.(1988). TheUseof
human beings in research: with special reference to clinical trials. Dordrecht ; London, Kluwer
Academicat29-46
9CunninghamandWilliams,TheLaboratoryRevolutioninMedicine.at2
10Ibid.at1
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