NSCI 301: ethical challenges in SCI clinical trials

relevant ethical guidance

• declaration of helsinki

• belmont report

• tri-council policy statement

• ethical principles: autonomy, beneficence, non-maleficence, justice

values and priorities

• relationality

• access

• identity

• intersectionality

• knowledge

• divergent values

• independence

relationality

• importance of support from peers, family and healthcare workers for wellbeing

• community integration: after SCI, how do patients reintegrate into their community?

access

importance of accessible support and services

identity

impact of SCI on roles in society

intersectionality

• variety of factors intersect to affect the experience of SCI

• being a woman and having SCI = impact vulnerability

knowledge

• important of accessible info and education about SCI affects a person’s experience

• SCI person wants to know abt the studies and be involved: stem cells, devices, brain computer interfaces

divergent values

• diverse and potentially conflicting priorities between patient and care-providers in care and rehab

• want bladder control (SCI person), but researcher has diff goals

independence

ability to fulfill aspects of daily living and self-management without external aid

ethics in clinical research

• voluntariness

• informed consent

• right to withdraw

• confidentiality

• accessibility

• values and priorities

• follow up safety

voluntariness

no coercion to participate in study

informed consent

risks and benefits

safety

participants not taken advantage of

SCI

• vv heterogeneous - difficult to study

• types: cervical (all 4 limbs), thoracic (bottom limbs + trunk stability), lumbar (bottom limbs)

physical consequences of SCI

• paralysis - loss of motor and sensory function

• loss of control over bowel and bladder function and sexual function

• pain

• susceptibility to infection

• affects other physiological functions: breathing and cardiovascular

social consequences of SCI

• loss of independence

• limited employment opportunities

• altered purpose/meaning of life

• personal and financial burden on individual and caregiver

• societal costs is roughly $2.7 billion

SCI pathophysiology stages

1. acute

2. intermediate

3. chronic

within 24 hours = SCI patient should be in trauma centre

acute

• 2 days after initial injury

• haemorrhage

• pro-inflammatory cytokine release

• inflammatory cell infiltration

• oedema

intermediate

• 2 days - 2 weeks after initial injury

• axonal dieback

• inhibitory proteoglycan deposition:

  • pro-inflammatory cascades lead to this

  • sticky substances that inhibit environment of degeneration

chronic

• 2+ weeks after

• wallerian degeneration

• formation of scar to precvent explosion

phase I of clinical trial

• safety

• safest tolerable dose

• side effects

• small pop

phase II of clinical trial

• efficacy

• most effective dose

• outcome measures

• larger pop

• biological interventions like stem cell therapies do not pass this phase bc potential risk of tumour formation, and invasive surgeries

phase III of clinical trial

• confirmation

• compare to other treatments

• adverse events

• control group

phase IV of clinical trial

• follow up

• market

• a lot fail and do not make it to this stage bc expensive

• mostly pharmaceutical companies get here bc they have the money

cost of clinical trials

100s of milions to billions of $

enrollment of clinical trials

• small pop

• strict criteria

clinical trials have

• low statistical power

• poor design

• single site

reasons to stop clinical trial

• safety: adverse events

• poor study design - low enrollment = lost money

• efficacy - insignificant results

• commercial reasons:

  • research budget shrinks

  • competitive products emerge (cheaper or more promising)

  • supply failures

  • pressures to end unproductive programs = cancer research is where the money at

SCI interventions

• drugs: help with inflammation, pain and axonal health

• stem cells: help with inflammation, regeneration and cell replacement

• devices: movement, pain , physical support

• biomaterials: regeneration

• surgery: limit damage, relieve pressure, nerve grafts

• combination is the solution

mend the gap

• biomaterial injected into a spinal cord lesion

• help axon grow by providing growth factors

• does not work on stem cels

aligning ethics for mend the gap

stem cells

• self-renewing and multi-potent properties:

  • regenerative potential

  • multiple targets

  • cell replacement

• types:

  • embryonic: ESCs

  • adult: MSCs

  • induced pluripotent: iPSCs

• ethical issues:

  • donor rights

  • safety

donor rights

• privacy, consent, property rights

• henrietta lacks (HeLA cells):

  • had cervical cancer

  • her cancer cells were removed and used to study all without her consent and compensation

safety - stem cells

• source of cells - especially embryonic need a large amount for each patient

• invasiveness

• formation of tumours

• lack of follow-up protocols after tumour formation

values and priorities

• chronic cervical vs thoracic SCI have diff views:

  • cervical: don’t wanna do stem cell treatment, but biomaterials does them wonders

  • thoracic: any improvement = worth the risk

case study: geron trial

• 1st trial using human embryonic STEM cells

• 2 weeks after injury

• transplanted 4/10 patients

• stopped after a year bc they wanted to transfer the resource to cancer research

• violation of declaration of helsinki = wellbeing of patients must take precedence over everything

medical tourism

• enhancement and treatment: cosmetic surgeries and unapproved stem cell treatments

• media

• regulations and enforcement - new law that requires medical clinics whose stem cell treatments are not FDA approved to post notices and provide handouts to patients warning them abt potential risk in 2017 — stem cells are allogenic so more ok

• stem cell clinics in the US - leading destination for medical tourism

biomaterials

• biologically compatible - less risk

• scaffold - helps axons grow

• support stem cells and neuronal growth

• e.g.:

  • collagen

  • fibrin

  • matrigel: extracellular matrices in the body

• ethical issue: safety

case study - inspire trial

• pros:

  • scaffold support for stem cell therapy - help cells grow

  • deliver combination treatments

• cons:

  • invasive

  • potentially requires 2nd surgery

  • worsens SCI

devices

• support mobility

• reduce pain

• aids rehab

• e.g.:

  • exoskeletons

  • electrical stimulation

  • brain computer interfaces

• ethical issues:

  • safety

  • access

neuralink

• brain computer interface

• ethics:

  • will everyone who needs one get one?

  • who determines that?

  • can it be hacked?

  • and if it gets hacked, whose fault is it

exoskeletons

• data collected from sensors and who owns the data

• fit narrow range of ppl

electrical stimulation

• invasive but vv promising

• clear balance of risk and benefit

cost to general society

• trial participants abandoned when trial fails:

  • violates risk-benefit contract between patients and sponsors

• loss of knowledge:

  • when trial fails = data not published = loss of public trust

• healthcare does not progress efficiently:

  • tax funded research doesn’t translate to societal benefits