ICAD New prevention technologies workshop

8/10/2019 ICAD New prevention technologies workshop

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New Prevention

TechnologiesWorkshop

Module 6:Ethics

WWW.ICAD-CISD.COM


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HUMAN RIGHTS ANDETHICAL CHALLENGES IN

NPT RESEARCH


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Overview of research ethics: origins, guidelines,principlesOverview of role of various players inbiomedical prevention research

Community engagement: models, challenges,vulnerability and targeted populationsDynamics of North-South researchCase study: Cambodia, Cameroon, Thai trials

Standard of prevention and care for trialparticipantsUse of ARVs for prevention vs treatment

OUTLINE


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What is Ethics?

Ethics is a way of understanding andexamining what is right and what iswrong

Bioethics is a way of understanding and

examining what is right and what iswrong in biomedical research andpractice.


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What is your understanding of thesewords ?

Respect

Harm Fairness

Activity


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Principles of Research Ethics

Respect for Persons

Beneficence/Non-MaleficenceJustice/Non-Exploitation


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Respect for Persons

Autonomy Says that each individual:

Is unique and free;Has the right and capacity to decide;Has value and dignity; andHas the right to informed consent.

Protection for vulnerable persons Special protections must be in place for those whosedecision making capacity is impaired or diminished,whether due to physical or social factors


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Beneficence/Non-Maleficence

Protection of the study participants is themost important responsibility of theresearcher

Researchers must:Protect the physical, mental and social well-

being of each research participant;Minimizes physical and social risks;Maximize the possible benefits; andRetain the community perspective.


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Beneficence/Non-Maleficence

ON BALANCE:

The research should generate moregood than harm; andRisks of research should be reasonablein light of the expected benefits to the

individual and to society.


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Justice/Non-Exploitation

The principle that calls for fairness in the conduct ofresearch is the principle of justice/non-exploitation

Research must:Ensure a fair distribution of risks and benefitsResearch should not be done in a communitythat is not likely to benefit from the result

Conduct equitable recruitment of researchparticipants; andProvide special protection for vulnerable groups.


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Participant Risks vs. Benefits

Biologic/PhysicalSocial/Emotional

From the product: sideeffects

From HIV/STI testingPartner issuesStigma

Improved access to

health careBetter prevention

Risk reduction counselingSTD treatmentCondoms

OtherCashSense of socialcontribution

RISKS BENEFITS


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Participants Have Said the Benefits ofParticipating in Microbicide Trials Include:

Access to medical services and regular health checks isconsidered the biggest benefit

Counseling about womens bodies, sexuality,reproductive tract infections, STIs, and HIVGood relationships with study staff

Feeling empowered; improved communication with male

partners and childrenAccess to study gel; improved sex due to gel

Contributing to a womens health cause: One is helpedbut is also helping others


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Participants Have Said the Risks andBurdens of Microbicide Trials Include:

HIV testing considered biggest burdenDiscomfort during pelvic examLong waiting times at clinicFeeling of loss at end of studyWorries about side effects


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Community Burdens and Benefits

Risks and Burdens Possible stigmaDiversion of local health personnel

Benefits Improved health infrastructureTrainingCommunity education on HIV/researchPreferential access to product if it proveseffective

ill i i i i i l i


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Will participating in trials increasepeoples risk of HIV?

Generally, no...People will become infected during the trial but not because of the trialPeople in both arms should have lower HIV prevalence thanpeople in the general community

Condoms only

`

Before trial During Trial

Condoms +placebo gel

Condoms +microbicide

(if it works)

Risk

Condom only


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InformedConsent

UndueInducement

TherapeuticMisconception

Equipoise

Important Ethics Concepts


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Equipoise is a state of genuine uncertainty ordoubt about whether one intervention ortreatment is superior to another

Equipoise is a necessary condition for clinicalresearch to be morally acceptableIf the scientific community knows that onetreatment is better than another, it would beconsidered unethical to withhold it

Questions remain, however, about how todecide when scientific or clinical consensusexists about the relative merits of differenttreatments

Equipoise


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Therapeutic misconception refers to thetendency of some research participants towrongly assume that whatever drug orintervention they are offered must work or be

beneficial (or why would it be offered?)It occurs when the goals of research andthose of therapy or health care become

confused in the participants mind.The therapeutic misconception is a majorthreat to informed consent.

Therapeutic Misconception


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Voluntary informed consent is the agreementgiven by a well-informed person who:

Has received the necessary information

expressed in spoken words and in writing;

Has adequately understood the information;and

Has made the choice to participate (or notparticipate) without coercion.

Voluntary Informed Consent


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Essential Elements for InformedConsent

Research description (what is being studied, what is theprocedure, who is sponsoring the study?);Risks of participating;Benefits of participating;Alternatives to participation, such as other studies orservices in the area;Assurance that information will be kept confidential;

Compensation for time, travel or possible harm;Contacts (whom to contact with questions/concerns);andVoluntary participation and withdrawal.


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Informed Consent, Contd

Adequate understanding includes the differencebetween research and health care

related concept: therapeutic misconception

After thinking seriously about the information, theperson can arrive at a decision without being forced,threatened or offered something so valuable thatfree choice is impossible

related concepts: coercion and undueinducement

Legal and moral agenda can sometimes


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Legal and moral agenda can sometimesconflict

Indemnify the research institutionVERSUS

Facilitate collaborative decision making

Length of formsDegree of technical information impartedWritten versus oral consentEmphasis on right to withdraw


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A ti it


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Discussion questions: What are good ways to convey this kindof information to people to ensure thatif they agree to participate in a study,they are giving informed consent?

How do you know if people haveunderstood the information and aremaking a free choice to participate?

Activity

Balancing respect for culture and respect for persons


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Balancing respect for culture and respect for persons

concept of individual autonomy may bein conflict with entrenched cultural normsor expectations

example: may be expected that a womans

husband has the right and authority tomake decisions regarding her health care

While recognizing local value and ethicalpluralisms, ethics is also concerned with

universal principles of conduct

Case Study Informed Consent


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A microbicide study is taking place in an African country.Focus groups in the community have shown that manywomen are interested in a microbicide because they are notable to negotiate condom use with their partners. Manywomen are coming to the study clinic to enroll in the trial.

A community advisory group is formed with communityleaders and representatives. A male member of the groupsays that he does not approve of the study because thewomen are not required to get the consent of their partnersto enroll.

A local womens group expresses concern that a womanwho enrolls in the trial without telling their partner risksbeing harmed if her partner finds out she is participating.

Case Study Informed Consent

ACTIVITY


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In some settings it is generally expected that awomans husband has the right and authorityto make decisions regarding her health care

In this instance, how should one balance respectfor persons with respect for culture?

Should sexual partners be involved? Are therecreative strategies for encouraging partnerengagement?

What might you recommend as an appropriateway to respect both of these values in thisinstance?

ACTIVITY


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OVERVIEW OF ROLEOF VARIOUSPLAYERS

Who?


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Who?

EthicsCommittees andReview Boards

Communityand Advocates

Researchersand Sponsors

EthicalResearch


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Who are the Players in HIV NPT


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Who are the Players in HIV NPTResearch?

Academic researchers and universitiesCommunity members and organizations,

community advisory boardsPrivate sector pharmaceutical and biotechcompanies

Government funders and regulatorsHealth care providers

d h


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Academic Researchers

Basic Researchers lead the scientific discovery and development of NPTcandidate concepts and products

Clinical Researchers

lead the clinical testing of candidate NPT products, testingefficacy as well as issues of acceptance and accessibilityestablish and maintain the highest standards of ethicalconduct of clinical trials

Social Researchers conduct research on acceptability, preparedness, access anddelivery issueswork alongside clinical research to understand usability andacceptance of NPTs


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Community Roles

develop community acceptance and preparedness for NPTsanticipate and mitigate stigma associated with trialraise awareness about the role community basedorganizations can play before, during and after trialsfacilitate clinical trial recruitmentincorporate NPTs into prevention education and trainingprograms for specific vulnerable populations

develop strategies for promoting and distributing NPTs onceavailableadvocate for investment in NPT research and development


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Private Sector

invest in research and development, manufacturing andproduction

technical innovation

establish clinical infrastructure (e.g., epidemiologicallaboratories, trials infrastructure) during the pre-clinicaldevelopment of the NPT that will be needed in clinicalresearch

translational research: generate data, clinical materials

Public Funding is Essential


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Why arent largepharmaceuticalcompanies

investing?Perceived lowprofitabilityLiability concernsLack of in-houseexpertiseUncertain regulatoryenvironment

Public Funding is EssentialGlobal Annual Microbicides R&DInvestment 2009 in USD$ millions

Source: HIV Vaccines and MicrobicidesResource Tracking Working Group

Government Funders and


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Government Funders andRegulators

provide funding for NPT research programs,academic researchers, conferencescoordinate domestic and global efforts

ensure that adequate clinical research facilitiesexistensure availability of properly trained staffhelp build public awareness and support forresearch and developmentachieve speedy and appropriate access once aNPT becomes available

H l h C P id


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Health Care Providers

Monitoring, prevention and control ofHIV/AIDS and STIs

Help with NPT delivery, education andaccessWith ARV-based NPTs, may need to be

prescribers


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COMMUNITYENGAGEMENT


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WHAT DO WE MEANBY COMMUNITY?

Competing & Changing


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p g g gDefinitions of Community

separate and overlapping groups of people who areinfected and affected by HIV in various ways

Good Participatory Practice, UNAIDS/AVAC

trial participants, their families and partners, otherlocal stakeholders, and service providers/communitygroups within the geographic parameters of the clinicaltrial location.

MDS Civil Society Working Group Report

the group of people who will participate in or arelikely to be affected by or have an influence on theconduct of the research.

HIV Prevention Trials Network, Community Program FAQs


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Locating Community


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Locating Community

When we talk about community, it isimportant to frame the discussion in

terms of:Who is included in the particular communitywe are discussing?

And distinguish which level we are referringto


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Trial Participants &

Study Staff refers to theindividuals directly

participating in thetrial, in someinstances theirpartner(s), and study

staff working at thetrial site.


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Host Community

refers to the individualsliving in the area of thetrial, their leaders, andcommunity-basedorganizations that serveor represent themdirectly. This can alsoinclude traditionalhealers, local radio, and

other communitystructures (includingCABs)


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National Stakeholders

describes anyone who has arole to play in the political,scientific, and socialenterprise of microbicidedevelopment in the larger,

national community.It includes political decision-makers, MoH, regulatorybodies, ethical review

committees, national NGOs,donors, national media, etc.

International


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Civil Society

refers to non-profit,organized, citizen-ledmovements or groupsinterested in the goals,process, and outcomes ofmicrobicide research, and/orin the rights of communitiesor research participants.

Civil society includesinternational or regionalNGOs (GCM/UNAIDS),internationalor media.

Issues of Power


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Power imbalances exist across multiple

lines: Principal investigators versus fieldstaff, Northern researchers versusSouthern; community versus researchenterprise; within communities and CABs

One goal of community involvement andNPT advocacy is to work towards reducedpower disparities

Pretending that power imbalances do notexist, however, breeds the worst form oftokenism

Why do we needCommunity Involvement?


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Ethical principle of beneficence

Maximize benefits and minimizes risks forparticipants and for host communities.

Minimize exposure to controversy and risk ofdisruption

Increase the transparency and accountability ofthe research to the community

Improve quality of trials , participant retention,adherence and accurate self-reporting:

ensuring trial procedures are acceptable toparticipants and other decision-makers

Strengthen local capacity and infrastructure

Community Involvement?

Community Involvement Strategies


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Community Involvement Strategies

Community advisory structures (CABs, CAGs, CACs,participant representatives)

Community preparedness

Community mappings

Radio & local media

Dramas and community events

Network community working groups

Cross-network community involvement


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Why is somuch blood

taken?

What do youdo with theleft overblood?

Are theneedlessafe/clean?


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No one wins when a trial is stopped for non -scientificreasons. But the only way to prevent this is to investthe time and resources needed to build the kind ofmutual trust on which collaborative partnerships can

be based. -Anna Forbes & Sanushka Mudaliar

Preventing Prevention Trial Failures: A Case Study and Lessons for FutureTrials from the 2004 Tenofovir Trial in Cambodia

We will not let Cambodians beused as guinea pigs


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used as guinea pigs Cambodian prime minister

Case Study: Cambodia Tenofovir Study


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y y

2003: Preparations begin for the conduct of a tenofovirPrEP study among sex workers in Phnom Penh

Many miscommunications and misunderstandingsbetween community groups and researchers

Protests at the International AIDS Conference, BangkokPress release by activist groups denounce trial

Media storm & negative reaction from Cambodia PM

2004: Trial halted by Cambodia government

Cameroon falls next


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Lessons Learned:Community Consultation


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Community Consultation

Must extend beyond local trialcommunity to include NGOs andother opinion leaders andstakeholders

Requires adequate lead time and aspecialized skill set;Must begin early when input canstill effect change

Demands separate line item in thebudgetFormative research cannotsubstitute for a consultativeprocess

Authentic Community Involvement


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~ Global Campaign for Microbicides

Partnership andMobilization

Researchimplementation exists

alongside specificprocess goals thatstrengthen the role

and capacity ofcommunity to

articulate and addressits own development

needs including futureresearch priorities.

Historical No involvementof communityexcept as poolfrom which todraw researchparticipants

Advisory Community

representativesprovide inputinto specificareas of the

study asrequested by the

research team

Collaborative Community

representativesand research

team cooperatein developing

andimplementing

the research

Evolution of Norms for Community Involvement in Research


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DYNAMICS OFNORTH-SOUTHRESEARCH

Researcher Obligations


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Ethically , researchers must provideparticipants with medical care andcompensation for study-related injuries Legally , researchers may not have to

provide treatment and compensation For example, US law only requires thatstudy participants be told what types ofcompensation or treatment will beavailable

Can implies Ought


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A persons duty to benefit another isrelated to his or her capacity to do so,whether financial or practical.

If a benefit cannot be provided for reasons of

practical constraint, the duty to do so isweakened.

Conversely, if a countrys wealth allows it toconfer a benefit on the inhabitants ofanother country, the wealthier country has astronger duty to provide that benefit

An alternative articulation ofCore Ethical Principles


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Core Ethical Principles

The duty to alleviate sufferingThe duty to show respect for persons

The duty to be sensitive to culturaldifferenceThe duty not to exploit the vulnerable or

less powerful(Nuffield Council on Bioethics, 2002)


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PUTTING IT ALLTOGETHER:

WHAT MAKES

RESEARCH ETHICAL?

a a es esearcEthical?


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Social or scientific valueScientific validityFair subject selectionFavorable risk-benefit ratioIndependent reviewInformed consent

Respect for potential and enrolled subjectsCollaborative partnership

(Emanual et al., JAMA, 283, 2000)

Seven Steps for Ethical Research


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1. Priorities: Did the study address a priority issue? Whose?

2. Planning: Was the study well designed to optimize the chances ofgenerating useful knowledge and protecting subjects?3. Permission : Was the project reviewed and cleared by the

relevant institutions? Did the investigators obtain informed

consent?4. Performance: Was the study conducted in a way that respectedthe rights of the subjects and minimized the risks to them?

5. Processing: Were the results correctly analyzed and interpreted?

6. Publication: Were the results published and disseminated?7. Programming: Have the findings been translated to policy and

action?


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STANDARD OFPREVENTION ANDCARE FOR TRIALPARTICIPANTS

Standard of Care


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The term Standard of care refers to thenature of the prevention and/or care that willbe provided to participants in research

the general care and treatment that

investigators agree to provide allparticipants in clinical researchthe quality of care that should be providedto people in the control arm of a RCT i.e.those that are not receiving theexperimental intervention

The Standard of Care Debate


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The appropriate Standard of Care in international trials hasbeen subject to intense discussion and debate

Debate heated up around controversial HIV trials to preventmother to child transmission in the developing world

Commentators questioned the ethics of trials that used aplacebo when an existing regimen 076 had been shown toreduce peri-natal transmission of HIV in the United States

Defenders argued that the 076 protocol was not relevant tothe health care needs or priorities of the developing world,because it could not viably be implemented


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Universal Standard Position


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I believe that our ethical standards should not dependon where the research is performed. Furthermore Ibelieve the nature of investigators responsibility forthe welfare of their subjects should not be influenced

by the political or economic conditions of the region. Inpractical terms any other position could lead to theexploitation of people in developing countries, in orderto conduct research that could not be performed in thesponsoring country.

Marcia Angell, Editor, NEJM

Ratcheting Up Standardl k l h ll l d d f


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As it is unlikely that an overall universal standard ofcare can be rapidly achieved in research projects indeveloping countries, the goal should be toimplement reasonable standards that aresignificantly higher than available in the host countryand closer to standards in the sponsoring country.These ideas should be applied in a way thatprogressively ratchets SOC upwards, both forsubsequent research projects and for local healthcare infrastructure through genuine partnerships

and capacity building, leaving participants and theircommunities better off after the trial than before.

Shapiro and Benatar, 2003

What does ethics guidance say?


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Individuals in the control arm must receive: An established effective intervention (CIOMS) The best current prophylactic, diagnostic and therapeuticmethod (Declaration of Helsinki, 2002)

Ideal: best proven therapy; Minimum: highest level of careattainable in light of the circumstances listed" (UNAIDSvaccine guidance)Ideal: best proven; Minimum: the best intervention availablefor the disease as part of the national health system (NuffieldCouncil)Highest achievable standard should be the goal ( Benatar &Singer, BMJ, 2000)


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Standard of prevention and care inbiomedical prevention trials


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p

Informed consent can be undermined by

(Undue) Inducement


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Informed consent can be undermined byincentives that lead to undue pressure,coercion or undue inducement toparticipateAn inducement may persuade an individual to

change his or her mind about entering aresearch project, but this in itself is notenough to make it inappropriateAn inducement becomes inappropriatewhen it causes a person to assume risks thatthey would ordinarily view as unacceptable

(Nuffield Council on Bioethics)

How Do You Decide If Its Undue?


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Harmfulness: the nature of the potential risks tothe participants health

Proportionality: whether the inducement is in

proportion to the risks and costs of researchVulnerability: whether prospective participants areespecially vulnerable to influence

Reciprocal Justice: someone who benefits from theinvestment and sacrifice of others owes themproportional recompense

access to all state of the art HIVrisk reduction methods


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Traditionally means sexual counseling and condomsNew HIV risk reduction methods should be added asthey are scientifically validatedWould that include a partially effective vaccine ormicrobicide when available? PrEP? Malecircumcision?Red herring: this requirement could make it difficult

(impossible?) to analyze results of HIV preventiontrialsUndue burden on researchers?


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STEP Trial


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Found enhanced susceptibility to HIV amongthose in the experimental arm = trial relatedharmCalls for enhanced obligation to patients for careand treatment follow-up monitoring of viralloads and ARVBUT no time limit was discussed generally

accepted as 5 years

Balancing methodological and ethical gold standards


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Should future trials exclude uncircumcisedmen?

Should trials offer/require/encouragecircumcision among male participants?


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Thai PrEP trialEthics Case Study

Thai PrEP Trial


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CDC trial in Thailand: examining the safety and efficacy oftenofovir as PrEPConducted in collaboration with the Bangkok MetropolitanAdministration and the Thailand Ministry of Public Healthis enrolling 2,400 HIV-negative intravenous drug users (IDUs) male and female at 17 drug treatment clinics in Bangkok Participants are recruited at the drug treatment clinics, atcommunity outreach sites, and through a peer referralprogram.No clean needles or needle exchange being provided toparticipants

1. Which ethical principles are potentially being

Discussion Questions


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p p p y gviolated in the Thai PrEP trial?

2. Should the researchers be expectedto provide needle exchange when suchprograms are not available in Thailand?

3. How could the trial have been designed tobe more ethical?

4. What impact do you think these ethicalconcerns have on the validity of the trialresults?


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Standard of CareHow do we achieve new ideals?


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Heightened sensitivity to exploitationAim for reasonable practical limitsRatchet the standard upwards

Build capacity through real partnershipsFollow the spirit of Declarations Avoid cook-book attitudes to ethics

Consider: context / safety / logistics / harmbenefit / sustainability


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The convergence of treatment andprevention


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Can Antiretroviral treatment provide the bestprevention intervention?


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In view of the potential effect of HAART on HIVtransmission, what would be the implications of analternative prevention-centred strategy for the use ofHAART? This approach would be based on the notion thatnew HIV infections are overwhelmingly contributed to byindex HIV-infected individuals who are not on HAART. Aprevention-centred approach would therefore argue thattreating 100% of HIV-infected individuals at once couldgreatly reduce HIV transmission. While this would be costly inthe short term, it could prove highly cost effective. Theshort-term cost of treatment of all HIV-infected individualswould be more than offset by the number of new infectionsthat it would prevent.


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DEBATEShould ARVs beprioritized for prevention

or for treatment?

PrEP Case Study


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