Ethical Issues in Vaccine Trials

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Ethical Issues in Vaccine Trials

• Three major concerns

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Three main ethical issues

• Standard of care for trial participants who
  become infected during the trial.
• Choice of comparator in future randomized
  controlled vaccine trials
• Post-trial obligations to provide vaccine shown
  to be efficacious

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1. Care and treatment for infected participants

• The best current treatment available anywhere
  in the world
• Beneficence Maximize benefits and minimize harm
  to research subjects
• Reciprocity People who make a significant
  contribution deserve something in return
• Justice as equality Treat like cases alike

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Ethical principles

• Beneficence
• The obligation to maximize benefits in research
  goes beyond the design of a trial and the conduct
  of the trial itself

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Ethical principles

• Reciprocity
• Subjects who become infected contribute
  importantly to the trial
• Without such data, an efficacy trial could draw
  no conclusions about the vaccine being studied
• People who contribute to an effort deserve
  something in return

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Justice as equality

• Treat like cases alike
• Subjects in U.S. or Europe who become infected
  have access to ART
• Subjects in resource-poor countries are similar
  in relevant respects
• Therefore, justice as equality calls for making
  ART available to all participants in vaccine
  trials, regardless of their geographical location

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Care and treatment

• Family members of participants
• If ART is provided to participants who become
  infected, can such treatment reasonably be
  withheld from infected partners and children of
  participants?
• A genuine ethical quandary

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Care and treatment

• Is an offer to potential participants to provide
  ART if they become infected an undue
  inducement?
• A flawed argument
• No one would enroll in the trial and then
  deliberately become infected in order to get ART

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Declaration of Helsinki

• Does not specify any obligations to provide
  medical treatment during research
• General statement of obligation
• It is the duty of the physician in medical
  research to protect the life, health, privacy,
  and dignity of the human subject
• Para. 10

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Highest attainable level of care

• UNAIDS Guidance Point 16 Care and treatment
• Care and treatment for HIV/AIDS should be
  provided to participants with the ideal being to
  provide the best proven therapy, and the minimum
  to provide the highest level of care attainable
  in the host country in light of circumstances
  specified.

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2. Choice of comparator

• When is it ethically acceptable for the control
  group to receive placebo?
• If the best scientific design requires placebo
  control, and the best ethics requires an
  established, effective intervention, how should
  this tension be resolved?

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Ethical use of placebo

• Undisputed When there is no established,
  effective intervention
• Generally accepted When withholding an
  established, effective intervention would cause
  only minor or temporary harm
• Inapplicable to future vaccine trials if current
  trials show moderate-to-high efficacy

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Ethically problematic cases

• Current or future trials show vaccine efficacy of
  30-50
• May placebo be used as a comparator?
• There is an established, effective vaccine but
  its use as a control would yield less than the
  best scientific results
• Tension between the highest scientific standards
  and the highest ethical standards

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UNAIDS Vaccine Guidance Document

• UNAIDS Vaccine Guidance Document
• As long as there is no known effective
  preventive HIV vaccine, a placebo control arm
  should be considered ethically acceptable in a
  phase IIItrial.
• Guidance point 11

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UNAIDS Vaccine Guidance Document

• Additional commentary (GP 11)
• Participants in the control arm of a future
  phase III HIV preventive vaccine trial should
  receive an HIV vaccine known to be safe and
  effectiveunless there are compelling scientific
  reasons which justify the use of placebo.

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Compelling scientific reasons to use placebo
(UNAIDS guidance)

• The effective HIV vaccine is not believed to be
  effective against the virus that is prevalent in
  the research population
• However, strong scientific evidence must be
  produced to support a claim that the effective
  vaccine is not effective in that population

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Compelling scientific reasons to use placebo
(UNAIDS guidance)

• There are convincing reasons to believe that the
  biological conditions that prevailed during the
  initial trial demonstrating efficacy were so
  different from the conditions in the proposed
  research population that the results of the
  initial trial cannot be directly applied to the
  research population under consideration

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3. What should be made available?

• Do sponsors, researchers, or ministries of health
  have an obligation to the community or country if
  a successful product results from a vaccine
  trial?
• Some current answers.

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Declaration of Helsinki 2000

• Medical research is only justified if there is a
  reasonable likelihood that the populations in
  which the research is carried out stand to
  benefit from the results of the research.
• Paragraph 19

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Declaration of Helsinki 2000

• Too vague to give clear guidance
• What are the criteria for determining the
  likelihood that the population will benefit?
• What degree of likelihood is necessary?

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CIOMS International Ethical Guidelines--10

• Before undertaking research in a population or
  community with limited resources, the sponsor and
  the researcher must make every effort to ensure
  that

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CIOMS Guideline 10

• 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 product developed will be made reasonably
  available to that population or community

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UNAIDS Guidance Document

• Any HIV preventive vaccine demonstrated to be
  safe and effective, as well as other knowledge
  and benefits resulting from HIV vaccine research,
  should be made available as soon as possible to
  all trial participantsas well as to other
  populations at high risk of HIV infection. Plans
  should be developed at the initial stages of HIV
  vaccine development to ensure such availability.

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Critics response

• An absolute requirement to provide effective
  interventions would act as an impediment to
  finding sponsors willing to support research in
  developing countries
• Beneficial research might therefore be delayed or
  avoided altogether, thus harming developing
  countries

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Reply to critics

• If there is little likelihood that successful
  results will be implemented where the research is
  conducted, then the research is not truly
  responsive to the populations health needs
• The population loses nothing if the research is
  not conducted, if the products will not be
  available anyway

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Conclusions

• International research is a global enterprise
  that should be governed by universal ethical
  standards
• Prior agreements to make safe and effective
  vaccines available to the populations in
  developing countries where they are tested can
  aid in preventing exploitation and contribute to
  global justice