Planning ahead: ethical considerations in study design

1
Planning ahead ethical considerations in study
design

• Paul KomesaroffDirectorMonash Centre for the
  Study of Ethics in Medicine and SocietyMonash
  University, Melbourne, Australia

2
Ethics and science cannot be separated

• Scientific projects are driven by ethical goals
• Ethical issues are not merely supplemental to the
  science but arise from within it
• Bad science is bad ethics

3

• A projects objectives may be ethically
  questionable
• The study design may raise ethical questions
• The methods themselves may generate ethical
  issues

4
Researchers and IRBs have ethical
responsibilities with respect to study purpose,
design and methods

• To scrutinize the goals of the project
• To ensure that it is scientifically valid
• To ensure that the conduct of the study will not
  lead to major ethical problems
• (Sleight P. J Intern Med. 2004 Feb255(2)151-8.)

5
Questions for researchers and IRBs from an
ethical perspective

• What are the underlying objectives of the
  project?
• Are these objectives clearly formulated?
• Is the study design sufficient to achieve the
  goals of the research?
• Who will the participants be?
• What will be the risks to the participants?
• Are the researchers competent to carry out the
  study?
• Do the researchers have any dualities that need
  to be examined?
• Are other issues raised by the methods or
  proposed protocol?
• How will data be analysed?
• How will results be disseminated?

6
A projects objectives may be ethically
questionable

• For example, research into
• Weapons of mass destruction
• Biological warfare
• Nuclear weapons
• Environmentally destructive technologies

7
Ethically controversial research an example

• The ethical content of research may be dependent
  on the social context.

8
Ethically controversial research an example

• Research into atebrin, a new anti-malarial agent,
  in Australia during World War II, involving
  junior servicemen infected with plasmodium
  falciparum and treated with the new drug or
  placebo
• This research was risky, involved vulnerable
  participants and consent was doubtful.
• However, it was judged socially acceptable as it
  served what was considered to be an important
  social purpose at the time.

9
Possible objectives of a project

• To increase understanding of a biological process
• To contribute to the treatment of disease
• To study the social causes or impact of a health
  problem
• To contribute to the development of a marketable
  product
• To test a hypothesis
• To collect pilot data to allow a preliminary
  assessment of a topic or develop a new method
• To provide training for students

10
Assessing whether the study design is adequate to
achieve the research goals

• A scientific question but an ethical
  responsibility
• Are there sufficient subjects to ensure adequate
  testing of the hypotheses?
• Are the controls adequate?
• Is the population the right one in which to test
  the questions?
• Has the study been designed to secure a
  particular outcome?

11
The study participants

• Who with the participants be?
• How will they be recruited?
• Will they belong to a vulnerable group?
• Are there special cultural issues that need to be
  considered?
• How will consent be obtained?

12
Consent

• The ethical and legal requirements of consent
  have two aspects
• Provision of information about the purpose,
  methods, demands, risks, inconveniences,
  discomforts, and possible outcomes of the
  research
• Exercise of a voluntary choice to participate.
• A third component - that of communication - is
  also essential

13
Participants with reduced capacity to consent

• Children and young people
• Persons with an intellectual or mental impairment
  
• Patients in emergency care
• Patients in intensive care
• Terminally ill people
• Unconscious persons
• Persons in dependent or unequal relationships
• Teachers and students
• Doctors and patients
• (J Med Philos. 2004 Jun29(3)351-78 Kopelman
  LM. Seedat S, Pienaar WP, Williams D, Stein DJ.
  Curr Psychiatry Rep. 2004 Aug6(4)262-7. Lind
  C, Anderson B, Oberle K. Nurs Ethics. 2003
  Sep10(5)504-11.)

14
Possible consequences of including vulnerable
populations

• Consent may be compromised
• The risk of adverse events may be greater
• There may be lack of attention to special needs
• An unfair burden may be placed on particular
  groups

15
Research involving particular cultural groups

• May raise special sensitivities related to the
  beliefs or customs of the group or their
  particular vulnerabilities.

16
Research involving particular cultural groups

• Example Research involving Australian Aboriginal
  people
• Consent may need to involve a collective
  component
• Recording of names and photographs of dead people
  may be culturally offensive
• There may be religious issues concerning use of
  tissue samples
• Ownership of intellectual property can be
  politically sensitive
• (Mooney G. Aust N Z J Public Health.
  200226(3)201-2. Holmes W, Stewart P, Garrow A,
  Anderson I, Thorpe L. Soc Sci Med. 2002
  Apr54(8)1267-79.)

17
Research involving particular cultural groups

• Example International HIV/AIDS research
• Often involves poor, illiterate, populations with
  limited access to local health care
• There is limited local surveillance or monitoring
  of the research process
• Local communities are often unlikely to receive
  any benefit from participation
• (Ahn MJ, Grimwood A, Schwarzwald H, Herman A. J
  Int Assoc Physicians AIDS Care (Chic Ill). 2003
  Apr-Jun2(2)81-7.)

18
Evaluation of risks to the participants

• A key question for researchers and IRBs
• May be difficult to decide
• May need specialised knowledge
• May be difficult to balance against possible
  benefits

19
Evaluation of risks

• Risks may be physical, psychological or social
• Dangers from drugs, devices or invasive
  procedures
• Costs, inconvenience, discomfort
• Exposure to legal or social consequences
• Revival of anxieties or traumatic memories
• Interference with staff duties
• Effects on other patients
• Sometimes can be quantified on the basis of
  previous evidence
• Phase I and II studies of a drug
• Personal experience of investigator
• Often data are limited or unreliable

20
Evaluation of risks

• Balancing of risks and benefits can be difficult
• Projects must carry some potential community
  benefit
• There are no guaranteed benefits to individual
  participants
• There is no ratio of risks and benefits
• The conclusion depends on a conversation about
  both scientific facts and ethical values
• (Weijer C. J Law Med Ethics. 2000
  Winter28(4)344-61 Beyrer C, Kass NE. Lancet.
  2002 Jul 20360(9328)246-51.)

21
Issues concerning researchers

• Researchers must be competent and dualities must
  be identified and managed
• Personal experience and understanding of
  investigators may be important
• Dualities may include
• Relationships with industry
• Roles as clinicians and researchers
• Direct or indirect payments
• Potential non-pecuniary benefits from research
• (Komesaroff PA et al. Endocrinology. 2004
  Jun145(6)3032-41)

22
Ethical issues arising out of the study
methodology

• Impact on medical treatment of patients
• Nature of treatment in comparison with existing
  best practice
• Actions that will be taken in relation to new
  information
• Use of placebo controls
• Issues arising in relation to genetic research
• Issues arising in qualitative research

23
Use of placebo controls

• Controversial question in public debates,
  especially in relation to revision of the
  Declaration of Helsinki.
• Issues concern alleged denial of proven effective
  treatment and exploitation of vulnerable groups
• Nonetheless, placebos may still be justified in
  certain circumstances
• Costs and scientific requirements of non-placebo
  studies may be prohibitive.
• (Saunders J, Wainwright P. Clin Med. 2003
  Sep-Oct3(5)435-9.)

24
Issues in genetic research

• A subject of extensive and intense public debate.
• Many issues, including
• Access to data bases and other genetic
  information
• Complexities of consent processes involving blood
  relations
• Implications of results for individuals and
  families, including with respect to prediction of
  medical conditions, possibilities of treatment
  and misuse of information
• (Knoppers BM, Chadwick R. Nat Rev Genet. 2005
  Jan6(1)75-9.)

25
Ethical issues in qualitative research

• Includes a variety of methodological approaches
  distinct from quantitative methodologies and both
  overlapping and distinctive ethical issues
• Ethical questions include
• Consent may need to be verbal
• Nature and representativeness of study
  populations
• Relationships between researchers and
  participants
• Risks of psychological and social harm
• Maintenance of confidentiality
• Publication issues
• (Fossey E, Harvey C, McDermott F, Davidson L.
  Aust N Z J Psychiatry. 2002 Dec36(6)717-32 Fam
  Pract. 1995 Mar12(1)104-14 Britten N, Jones R,
  Murphy E, Stacy R. Fam Pract. 1996
  Apr13(2)208.)

26
Analysis and publication of data

• Is there a Data and Safety Monitoring Board?
• Who are the members of this Board?
• Who will be responsible for analysis?
• Will all the investigators have access to
  consolidated data?
• Are there dualities of interests that need to be
  managed in relation to data analysis and
  publication?
• How will data be analysed?
• Will trial participants be provided with study
  results?
• Is there a commitment to publication of data,
  regardless of results?
• (Jones AH and McLellan F. (Baltimore, Johns
  Hopkins, 2000))

27
Questions for researchers and IRBs from an
ethical perspective

• What are the underlying objectives of the
  project?
• Are these objectives clearly formulated?
• Is the study design sufficient to achieve the
  goals of the research?
• Who will the participants be?
• What will be the risks to the participants?
• Are the researchers competent to carry out the
  study?
• Do the researchers have any dualities that need
  to be examined?
• Are other issues raised by the methods or
  proposed protocol?
• How will data be analysed?
• How will results be disseminated?

28
Summary

• Ethics and science cannot be separated bad
  science is bad ethics
• The design and methods themselves may generate
  ethical issues
• Researchers and IRBs have ethical
  responsibilities with respect to study design
• Ethical considerations must be built into
  research projects from the beginning

29

30

• Study design may not meet the projects purpose
• Hypotheses may not be adequately formulated
• Methods may be inadequate to test hypotheses
• The methods themselves may generate problems
• Risks to participants
• Issues in recruitment
• Conflicts of interest
• Privacy issues

31
Ways in which pharmaceutical studies can be
distorted

• Drug tested on population in which positive
  outcome is most likely
• New drug tested versus placebo or the worst
  alternative
• Highest tolerable doses tested to prove efficacy
• Lowest dose tested to prove safety
• Many outcome measures so that statistical
  significance is easy to demonstrate
• Misleading analysis or data presentation
• (Bero, Int J Technol Assess Health Care 1996 12
  209-237)