1 Informed consent Bernard Lo, M.D. August 11 and 12, 2010.

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Informed consent

Bernard Lo, M.D.

August 11 and 12, 2010

Neonatal blood samples

Screen for birth defects Required by law Parental consent not required

Later used for research on Preterm birth Environmental levels of pesticides Gene-environment interactions (smoking,

folic acid, cleft palate)2

Questions for audience

Do regulations permit research be

carried out on leftover neonatal spots

without consent? Yes /No / Unsure

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Should regulations permit research be

carried out on leftover neonatal spots

without consent? Yes /No / Unsure

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Neonatal blood samples

Parents in Texas sued over storage of

samples for for research without

consent

2002 Texas law allows opt-out

5.3 million samples from before 2002

destroyed

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Use of neonatal blood spots for research

Permitted under federal regulations

Ethically contested

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Outline for today

What does informed and voluntary

consent require?

How can consent be improved?

What are exceptions to consent? Why are some exceptions in regulations

ethically problematic?

Why is consent needed?

Research compared to clinical care Risks and benefits uncertain Risk/benefit balance less favorable Purpose is not to benefit participants

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Rationale for informed consent

Respect for values and choices of

subjects

Deter research with unacceptable risks

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After signing consent forms, do most

participants understand key features of

study?

Do IRB modifications improve

consent?

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1. HIV prevention trial

RCT of diaphragm + gel vs. diaphragm

+ placebo in women in Africa at risk for

HIV infection Both arms receive free condoms

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What must researchers disclose?

Nature and purpose of research

Research procedures, risks, benefits Unforeseeable risks

Participation voluntary, may

discontinue

IRB template

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Why is informed consent difficult?

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Participants commonly misunderstand Not understand how RCT differs from

clinical care Believe that study interventions are

• Standard therapy

• Best treatment for condition

• No additional risks

• For their personal benefit

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Participants commonly misunderstand Basic features of trial design

• May be in control group• Randomization• Therapeutic options restricted by study design

rather than individualized for them

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Vulnerable participants Low health literacy, low literacy Poverty, few options

Cultural context No informed consent in clinical care No acknowledgement of medical

uncertainty

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How can informed consent be enhanced?

Empirical studies Spend more time talking to participants Questions and feedback Shorter, simpler consent forms Multimedia -- mixed evidence

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Practical suggestions Take point of view of participant Use simple language that 8th grader can

understand Explain how RCT differs from clinical care Invite questions

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Focus on comprehension by

participant, not consent forms Administer questionnaire to ensure

appreciation of key aspects of study

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What is essential for participants to comprehend?

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Could still get HIV

Don’t know whether intervention works

May not get active intervention

Keep using condoms every time

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May refuse to participate

May withdraw from study

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Why is voluntary consent difficult?

Hard to say no to persons in power Defer to husband or father Relationship to investigator

• Student

• Employee

Undue monetary influence

Research participants who may lack decision-making capacity

Persons receiving CPR, ICU care

Severe dementia

Severe psychiatric illness

Young children

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Concerns about participants who lack decision-making capacity

Not appreciate risks

Not able to refuse

Might be subjected to risks that

competent persons would refuse

Options if lack decision-making capacity

Exclude from trials But lack evidence safety and effectiveness

of treatments

Additional protections

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Additional protections if lack decision-making capacity

Formal assessment of decision-making

capacity

Permission from surrogate

Assent of participant

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Additional protections for vulnerable partcipants

Closer monitoring for adverse effects

Subject advocate who can withdraw

participant from study

IRB include persons familiar with the

condition that impairs capacity

Research advance directives


Without consent, may researcher

Use EMR to study whether patients

have worse outcomes if admitted over

weekend?

Use leftover cancer tissue to identify

prognostic markers?

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Ethical rationale for no consent

Very low risk No physical risks Confidentiality the main risk Cannot be breached if not identifiable

Benefits of research >> risks

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Ethical rationale for no consent

No one would or should object if asked Cancer tissue would be discarded Leftover tubes of blood

Impracticable to get consent Could not carry out important study

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Consent not required

1. Not human subjects research No IRB review

2. Exempt from human subjects

regulations

3. Qualifies for waiver

What is human subjects research?

Interact with person OR

Use identifiable private information Not human subjects research if data and

materials cannot be identified Examples of tissue from cancer surgery

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1. Not human subjects research

De-identified data and materials

Coded data and materials, researcher

cannot access keys to code

None of 18 HIPAA identifiers Code may be retained by database or

biobank

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2. Exempt from federal regulations

Most survey and interview research Unless subjects can be identified and

responses could put respondents at risk• Not if ask about illegal activities, sensitive or

private topics

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2. Exempt from federal regulations

Existing data or materials Publicly available Existing data or specimens if researcher

records information in manner than subjects cannot be identified

• Can look at medical records

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Studies that require identifiers

Link specimens with clinical records

Prognostic markers in cancer HER2/neu overexpression = poor prognosis Trastuzumab effective only in patients who

overexpress HER2/neu

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3. Waiver of consent

Minimal risk

Not adversely affect rights and welfare

Could not be practicably carried out

IRB may allow identifiable data to be

used without consent Use identifiers to link different databases

Research with cancer specimens

Not human subjects research if Completely de-identified Coded and researcher has no access to key Can determine prevalence of marker

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Neonatal spots

Not human subjects research if Completely de-identified Coded and researcher has no access to key

Waiver of consent Can link spots to medical records

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Neonatal spots

Permissible in regulations

Approved by IRBs

But still problematic

New standard is to offer opt-out for

research

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Do regulations permit whole genome

sequencing on de-identified materials? Yes /No / Unsure

Should regulations permit whole

genome sequencing on de-identified

materials? Yes /No / Unsure

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Re-identification in whole genomic sequencing

Reference samples in forensic

databases DOJ has 8.3 million profiles STRs at 13 locations Full genome sequence yields DOJ

identifiers

Whole genome sequence an overt identifier?

Need access to DOJ database

Is access to DOJ identifiers more

secure than access to SSN?

May need to rethink concept of “de-

identified” samples

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Concerns about whole genome sequencing

Subject may consider information very

private and sensitive

Privacy concerns access to

information about self May not want others to access Even if identity not explicitly known

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Concerns about whole genome sequencing

Some donors may object When giving blanket consent for research,

donors did not consider this If donors had been told, would they object?

Respect donors who have strong

objections

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Genetics of criminal behavior Match DOJ database with neonatal blood

spots without consent

Do regulations permit this? Yes /No / Unsure

Should regulations permit this? Yes /No / Unsure

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Objections to certain research on existing samples

Genetics of criminal and antisocial

behavior Stigmatize vulnerable populations Undermine individual responsibility

Human evolution

Derivation of embryonic stem cells

from IVF embryos50

Options

Sensitive research only with express

consent IRB determination of “sensitive”

More specific consent at donation

Re-consent participants? Make research much more difficult

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Take home message

Consent is important but challenging

Important exceptions to consent

permitted in federal regulations But some exceptions ethically contested Ethical standards may be stricter than

regulatory requirements Ultimate researcher is repsonsible

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1 Informed consent Bernard Lo, M.D. August 11 and 12, 2010.

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