Ethical Issues in HIV Vaccine Trial (Notes)

7/31/2019 Ethical Issues in HIV Vaccine Trial (Notes)

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ETHICAL CONSIDERATION IN

INTERNATIONAL HIV

VACCINE TRIALS

An Ethical analysis of HIV vaccine

trials


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IMPORTANT TERMINOLOGIES

For the sake of clear and sound

understanding of our discussion..


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AIDS (acquired immunodeficiency syndrome) isa disease caused by a virus called HIV (HumanImmunodeficiency Virus).

VACCINE

A biological preparation that typically contains

substances with antigenic properties thatresembles a disease-causing microorganism, andis often made from weakened or killed forms ofthe microbe, its toxins or one of its surfaceproteins. The agent induces an immune

response to recognize the agent as foreign,destroy it, and "remember" it, so that theimmune system can more easily recognize anddestroy any of these microorganisms that it later

encounters.


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VACCINE EFFICACY

The effectiveness of a vaccine, or how well it

works. Can be defined as the reduction in theincidence of a disease among people who have

received a vaccine compared to the incidence in

unvaccinated people."Efficacy" is used in clinicaltrial settings, whereas "effectiveness" is used in

real world (not carefully controlled) settings.

PLACEBO

IMMUNOGENICITY

INCIDENCE


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RISK BEHAVIOUR

CANDIDATE VACCINEAn experimental vacccine used in a trial

VIRAL LOAD

A measure of the severity of a viral infection,and can be calculated by estimating

the amount of virus in an involved body fluid.

For example, it can be given in RNA copiesper milliliter of blood plasma.


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THE URGENCY TO DEVELOP SAFE,

EFFECTIVE & GLOBALLY ACCESSIBLE HIV

VACCINE

What makes HIV vaccine so imperative ?


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1. The HIV pandemic

Global prevalence of disease and death related to

HIV is increasing at alarming rate

HIV is the most important infectious disease

AIDS is now the major cause of death in Africa,and 4th worldwide

More than 16,000 HIV infections occur everyday

Two thirds of all adults and children with HIV/AIDSlive in sub-Saharan Africa, where the epidemic has

drastically reduced life expectancy


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The International AIDS Vaccine Initiative (IAVI)projects that a vaccine with just 50% efficacy

administered to 30% of the population ofdeveloping countries between 2015 and 2030would prevent approximately a quarter of theinfections that would otherwise occur.

Without a vaccine, the number of new infectionsper year could increase from 6 million to 10million by 2030.

Given these discouraging statistics and

projections, the development of a safe andeffective HIV vaccine remains a critical but elusivegoal.


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2. The inaccessibility to the most

effective treatment

Antiretroviral Medication

Complicated to administer

Standard antiretroviral therapy (ART) consists of thecombination of at least three antiretroviral (ARV) drugs tomaximally suppress the HIV virus and stop the progressionof HIV disease.

Require close monitoring

Cause adverse side effects

diarrhoea, nausea, vomitting, rash, lipodystrophy (weightloss, lipid abnormalities, (abacavir in RV) increased risk ofheart attack

Extremely costly


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3. Burden of disease is greatest in

poorest countries More than 95% of all HIV infections occur in developing

countries

Of the 33.3 million people living with HIV/AIDS acrossthe world, 22.5 million are in Africa.

Africa is home to two out of every 3 people living withHIV/AIDS

South Africa also has one of the highest numbers of

children under 15 living with HIV/AIDS in the world;estimates range from 180,000 to 280,000.

South Africa has been hardest hit by the AIDSpandemic. One in five adults is HIV positive.


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PHASES OF TESTING AND CLINICAL

TRIALS

Pre-clinical Phase I Phase II Phase III


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Pre-Clinical Trials

Animal trials are also known as pre-clinical trials.These often include mice, rabbits and rhesusmacaques. But no matter how much we learnand study in animal models, only people becomeinfected with HUMAN immunodeficiency virus.Since no animals have the same immune systemsas humans, the only way to prove a vaccine'seffectiveness is to test in people, so ultimately wehave to move forward into human trials. Very fewvaccines reach this point.


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Phase I Trials

Phase I trials are generally small (less numberof healthy, uninfected participants at low risk

of HIV infection than 100 participants) and

designed to see if the vaccine is safe. Phase Itrials usually last 12-18 months.


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Phase II Trials

The goals of Phase II trials are usually to learnmore about vaccine safety and to see if thevaccine generates an immune response. Phase II

trials, which involve hundreds of participants,occur only after the experimental vaccine isshown to be safe in a smaller Phase Itrial. Questions about the right dose and the

scheduling of injections can usually be furthersorted out here. Phase II trials can last 2 or moreyears.


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Phase III Trials

After a successful Phase II trial, a Phase III trial

involves several thousand high-risk volunteers

to further assess if the vaccine works in

preventing HIV infection. Phase III trials can

last 3-5 years.


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ETHICAL CONSIDERATIONS IN HIV

PREVENTIVE VACCINE RESEARCH

Suggested guidance.


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1. HIV vaccines development

Sufficient capacity and incentives should bedeveloped to foster the early and ethicaldevelopment of effective vaccines.


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2. Vaccine availability

Any HIV preventive vaccine demonstrated to besafe and effective, as well as other knowledgeand benefits resulting from HIV vaccine research,

should be made available as soon aspossible toall participants in the trials on which it wastested, as well as to other populations at high riskof HIV infection.

Plans should be developed at the initial stages ofHIV vaccine development to ensure suchavailability.


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3. Capacity building

Strategies should be implemented to build

capacity in host countries and communities so

that they can practice meaningful self-

determination in vaccine development, canensure the scientific and ethical conduct of

vaccine development, and can function as

equal partners with sponsors and others in acollaborative process.


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4. Research protocols and study

populations

In order to conduct HIV vaccine research in an

ethically acceptable manner, the research

protocol should be scientifically appropriate,

and the desired outcome of the proposed

research should potentially benefit the

population from which research participantsare drawn.


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5. Community participation

To ensure the ethical and scientific quality of

proposed research, its relevance to the

affected community, and its acceptance by theaffected community representatives should be

involved in an early and sustained manner in

the design, development, implementations,and distribution of results of HIV vaccine

research


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6. Scientific and ethical review

HIV preventive vaccine trials should only be

carried out in countries and communities thathave the capacity to conduct appropriate

independent and competent scientific and

ethical review.


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7. Vulnerable populations

Where relevant, the research protocol should

describe the social contexts of a proposed

research population that create conditions for

possible exploitation or increased vulnerability

among potential research participants, as well

as the steps that will be taken to overcome

the and protect the dignity, safety , andwelfare of the participants.


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8. Clinical trial phases

As phases |, ||, ||| in the clinical

development of a preventive vaccine all have

their own particular scientific requirements

and specific ethical challenges, the choice ofstudy populations for each trial phase should

be justified in advance in scientific and ethical

terms in all cases. Early phase clinical trials should take place in

sponsor (developed) countries, unless there

are specific scientific and public health


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9. Potential harms

The nature, magnitude and probability of allpotential harms resulting from participation inan HIV preventive vaccine trial should be

specified in the research protocol as fully ascan be reasonably done, including provisionfor the highest level of care to participantswho experience adverse reactions to the

vaccine, compensation for injury related tothe research, and referral to psychosocial andlegal support.


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10.Benefits

The research protocol should outline the

benefits that persons participating in HIVpreventive vaccine trials should experience as

a result of their participation.


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11. Control group

As long as there is no known effective HIV

preventive vaccine a placebo control arm

should be considered ethically acceptable in aphase ||| HIV preventive vaccine trial.

Placebo-controlled vaccine trials are ethically

acceptable as long as there is no knowneffective HIV preventive vaccine


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12. Informed consent

Independent and informed consent based on

complete, accurate, and appropriately

conveyed and understood information shouldbe obtained from each individual while being

screened for eligibility for participation in an

HIV preventive vaccine trial, and beforehe/she is actually enrolled in the trial.


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13. Informed consent special

measures

Special measures should be taken to protectpersons who are, or may be, limited in their

ability to provide informed consent due to

their social or legal status.


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14. Risk-reduction interventions

Appropriate risk-reduction counseling and

access to prevention methods should beprovided to all vaccine trial participants, with

new methods being added as they are

discovered and validated.


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15. Monitoring informed consent and

interventions

A plan for monitoring the initial and

continuing adequacy of the informed consentprocess and risk-reduction interventions,

including counseling and access to prevention

methods, should be agreed upon before the

trial commences


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16. Care and treatment

Care and treatment for HIV/AIDS and its

associated complications should be provided

to participants in HIV preventive vaccine trials,with the ideal being to provide the best

proven therapy, and the minimum to provide

the highest level of care attainable in the hostcountry.


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17. Women

As women, including those who are

potentially pregnant, pregnant, or breast-

feeding, should be recipients of future HIVpreventive vaccines, women should be

included in clinical trials in order to verify

safety, immunogenicity, and efficacy fromtheir standpoint.


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18. Children

As children should be recipients of future HIV

preventive vaccines, children should beincluded in clinical trials in order to verify

safety, immunogenicity, and efficacy from

their standpoint.


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DIFFICULTIES IN DEVELOPINGEFFECTIVE HIV VACCINE

Challenges faced by researchers


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1. HIV is a retrovirus

its genetic information is contained in RNA

instead of DNA.

Currently, no vaccines against human

retroviruses exist, so researchers lack prior

models from which to work


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2. Antiretroviral drugs, the most effective

treatment strategy currently available,

decrease a patient's viral load and delay the

development of AIDS, but they do not

eliminate HIV from the body. As a result,scientists have no examples of successful

immune responses to guide them in vaccine

development.


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3. lack ofsuitable animal models on which to

test vaccines before initiating trials with

humans. Experiments currently involve

chimpanzees infected with HIV and monkeys

infected with Simian Immunodeficiency Virus(SIV), a related virus. However, vaccine

candidates have invoked different responses

in each animal model.


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4. HIV's genetic variability and geographical

distribution.

There are nine subtypes, of the virus. Viruses

from different subtypes can recombine to

create new hybrid viruses, known as

circulating recombinant forms (CRFs), which

also infect humans.

Subtypes and CRFs have different geographical

distributions.

For example, subtype B is most prevalent in

the Americas, whereas subtypes C and E are

the major causes of HIV/AIDS in Africa and


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5. Need to be conducted in populations with

high incidence of HIV infections, namely

developing countries

- to produce valid and timely results


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ETHICAL ANALYSIS

1. Type of vaccine used

2. Standard of Care

3. Social Consequences

4. Conflicting interests

5. Enrolling vulnerable participants


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1. TYPE OF VACCINE USED

An ethical analysis


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TYPE OF VACCINE USED

most scientists believe that two classical approaches to

developing viral vaccines, using whole inactivated orlive-attenuated (weakened) viruses, cannot beemployed for safety and ethical reasons.

- During the mid- to late 1990s, controversy arose over

attempts to introduce a live-attenuated HIV vaccine,thought to be particularly dangerous due to its potentialto mutate and cause AIDS or other diseases.

- Experiments with primates showed that some

macaques who were given the candidate vaccineeventually developed an AIDS-like syndrome. This workalso suggested that the strains used in the vaccinescould be deadly to individuals with immature immune

systems.


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In trials of other vaccines, however, live-

attenuated vaccines against other infections have

provided better protection of those immunizedbecause they can stimulate a more substantial

and broad-based immune response for example

in H1N1, rubella, TB

However, it can be argued from an ethical

standpoint that it would be permissible to use a

live-attenuated HIV vaccine with the potential to

save millions of lives worldwide, even if acomparatively small number of people were at

risk of infection from the vaccine itself


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2. STANDARD OF CARE

An ethical analysis


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STANDARD OF CARE

Inability of Worldwide, scientists, ethicists, researchsponsors, and governments to reach consensus onaccepted standard of care for trial participants whocontract HIV during the course of a clinical trial aninevitable occurrence among the high-risk populations

in which most HIV vaccine research is conducted. Factors such as time, duration, and severity of the

disease are considered when researchers explore theprovision of medical care during a clinical trial.

The situation is complicated further when the diseaseis a chronic rather than acute condition as in HIV

and when the trials are held in resource-constrainedenvironments, as is the case of clinical trials held indeveloping countries


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PRO

it is morally unacceptable to allow patients toreceive less-than-optimal treatment, particularlywhen such treatments are known to be safe andeffective.

Rich countries sponsoring research in poorercountries have greater access to resources andare therefore ethically obligated to contribute to

sustainable improvements in the overall health ofdeveloping nations, not simply tending toindividual outcomes of research subjects.


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Generally, all parties believe that some

medical care beyond the specific requirements

of the research protocol should be provided toclinical trial participants. The majority opinion

is that because communities and individuals

participating in trials "are contributing toknowledge that is a global public good, [they]

should benefit in return.

The issue is what level of care should beprovided, by whom, and for how long.


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AGAINST

1. One option is the provision of the best treatment currentlyin existence worldwide - namely lifelong use ofantiretroviral drugs (ARVs)

As of 2006, the current cost of highly active antiretroviraltreatment (HAART), the standard drug regimen for those

infected with HIV, was estimated to be $730 per patient-year

Clinical trials conducted in America or Europe wouldrequire that infected participants receive the best availablecare, a lifetime regimen of anti-retroviral drugs, but for

similar trials held in developing countries, the prospect ofsuch care is dim at present.

Market prices for these drugs are often many times higher,particularly in the United States


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2. Treatment of HIV/AIDS is much more thanpurchasing and supplying medications

Frequent follow-up and monitoring of patientsare required due to the high prevalence of sideeffects from HAART and the inevitabledevelopment of drug resistance.

Developing countries and even clinical trial sitesoften lack the infrastructure to carry out this typeof surveillance on a sustainable basis.

Once the trial ends and researchers return totheir home countries, ongoing treatment in thehost countries would have to be continued byanother entity, the identity of which is unclear.


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3. One consequence of ensuring lifetime ARV

therapy to infected trial participants is a sharp

decrease in the scientific community(researchers)'s ability to conduct future HIV

vaccine clinical trials.

Funding and infrastructure are insufficient for full

provision of such care.

manufacturers' and other trial sponsors'

incentives to conduct essential research in

developing countries would quickly erode.

High costs are likely to deter sponsors,

researchers, and local health authorities from

initiating innovative and more ambitious projects.


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4. equity issues arises from provision oftreatment

Community and familial relations couldbecome strained if research volunteers receivebetter medical care than their neighbors orrelatives.

the promise of superior medical care couldbecome an undue incentive to participate inclinical trials.

well-resourced, research-sponsored care in anotherwise impoverished healthcare facility isan example of global health inequities.


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3. SOCIAL CONSEQUENCES OF HIVINFECTION

An ethical analysis


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Social effects of HIV vaccine

Some vaccine candidates may cause you to

appear HIV positive

Volunteers participating in HIV vaccine trials

may be falsely identified as HIV-positivesimply through

1. their association with trial

2. by developing falsely positive HIV antibody

test

Volunteers will be counseled to only get HIV

testin at the trial site because the site will


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Some people have experienced discrimination

when they told others that they were

participating in clinical research for an HIVvaccine.

No medical side effects or problems are

associated with appearing HIV infected oncertain tests. However, others may treat

volunteers unfairly if the experimental vaccine

causes them to appear HIV positive. Participants will not be able to donate blood

and they may also have difficulties with:

getting insurance, hospitalization, traveling to


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4. CONFLICTING INTERESTS

An ethical analysis

Conflicts of Interest


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Conflicts of Interest

health care providers gain prestige, grants, and promotionsthrough their research and publication of their work.Accordingly, they have a personal interest in recruiting andmaintaining participants in their studies.

However, some conflicting interests, particularly financial

ones, create ethical problems because they may influencethe numerous decisions researchers make over the courseof a study.

For example, such interests may lead researchers tooverestimate the benefits of a study, underestimate the

risks, fail to objectively review existing evidence, and, ifnecessary, halt an on-going study.
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5. ENROLLING VULNERABLEPARTICIPANTS

An ethical analysis


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VULNERABLE PARTICIPANTS

Adolescents

participating age from 12 to 18

Women


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1. Informed consent consent comes from parents. Mostparents wont let their child to participate in vaccine trials.

2. Protected from harm no actual guarantee that these

people will be protected from harm.3. Right to withdraw participating in vaccine trials meansthat the participant will have to live with theconsequences or side effects for the rest of their life.Theres no right to withdraw.

4. Privacy HIV AIDS is a stigmatized disease related to sex,blood and death. Those who participated would have tolive with the assumption from the community; e.g:homosexual, commercial sex, etc.

5. Discrimination, violence, and social rejection are often

experienced by adolescents and women when their HIVstatus to be exposed to partners and family members.


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OBSTACLES TO PARENTALCONSENT

Study case : Participation of Adolescents in HIV vaccine trials in South

Africa


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Obstacles to Parental Consent

Child-headed households

- orphans, children without resident adult

guardians

Many of adolescents attending the prenatal

and family planning clinics dont live with

parents


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CONCLUSION

CLOSING: Volunteers in clinical trials cannot getHIV infection or AIDS by receiving anexperimental vaccine.

An experimental vaccine must successfullycomplete at least three stages of testing in peoplebefore it can be licensed. Human clinical trials areregulated by strict ethical and scientific controls,and occur at specialized research centers aroundthe world.

Ethical Issues in HIV Vaccine Trial (Notes)

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