BMET3921/BMET9921

Biomedical Design &

Technology
Week 3: Ethical, Clinical, and Regulatory
Considerations

Dr Sandhya Clement
Associate Lecturer
School of Biomedical Engineering

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This Week

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 This Week – Lecture
– Relationship between ethical, clinical, and regulatory
considerations
– Ethical considerations in research and development
– Clinical workflows
– Regulatory issues and clinical trials

– Review Quiz: available during the week

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 Live Guest Lectures Week 3
– Alex Patterson
Senior Director Clinical Safety and Compliance at ResMed
&
– Priyanshu Gupta
Senior Product Manager at ResMed

Topic: What clinical evidence do you need to support a product

launch?

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 This Week – Workshop
– Update your tutor on team progress
– Should have identified key references by now
– Some references would have been read
– Requirements would start appearing
– Some ideas may have formed
– Clarify key questions
– Make appointments for longer meetings
– Start activity – see Week 3 page on Canvas
– The activity will continue with some modifications in Week 4

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Ethical, clinical, and regulatory considerations

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Ethical, clinical, and regulatory considerations
Where do they come from?

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 Pillars of Medical Device/Technology Development

Safety Effectiveness Efficacy

Expectation that Performance Performance
users and others under “real under ideal and
will be kept free world” controlled
from harm circumstances circumstances

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 Competing Needs
– Safeguard public health and safety
– Allow and incentivise innovative and beneficial new products to
reach market quickly
– Improve clinical practice
– Limit workflow disruption

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 WHO Development of Medical Devices
– Regulation and management
highly related to assessment
– Framework also considers:
– Effectiveness
– Adverse events
– Safe use
– Policy development about how
to prioritise and select
technology

Health technology assessment of medical devices, WHO Medical device technical series, 2011.
http://apps.who.int/iris/bitstream/10665/44564/1/9789241501361_eng.pdf
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 Three Components
– Regulation
– Define requirements for device design, development, and manufacture
with the purpose of ensuring the devices that reach the public are safe
and effective
– Clinical practice
– Considerations on efficacy and cost-effectiveness
– Ethics
– Moral principles to govern behaviour and activities during device
design, development, testing, and use

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 Difficult Questions
– Level of evidence required to prove safety and efficacy
– Will too high a level of evidence slow benefits from flowing to patients?
– Will too low a level of evidence mean poor solutions get translated
faster?
– What level of risk is acceptable for degree of efficacy?
– Considerations
– Scientific evidence
– Human judgements

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 Health Technology Diffusion (Natural Lifecycle)

* *

Health technology assessment of medical devices, WHO Medical device technical series, 2011.
The University of Sydney http://apps.who.int/iris/bitstream/10665/44564/1/9789241501361_eng.pdf Page 13
Health Technology Assessment (HTA) at Different Stages
– Technology Research and Development
– Rigorous scientific evaluation
– Sample or case scenario
– Simulation and prototypes
– Clinical evaluation
– Experimental and Innovative Technology (Clinical Research)
– Control group and randomised trials
– Ethics
– General Use (Clinical Use)
– Ethics and Governance
– Patient trials
– Key Performance Indicators (KPIs)

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 Australian Government Regulatory Process (HTA)

http://www.health.gov.au/internet/hta/publishing.nsf/Content/home-1
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 From R&D to Implementation
Questions to ask

Health technology assessment of medical devices, WHO Medical device technical series, 2011.
The University of Sydney http://apps.who.int/iris/bitstream/10665/44564/1/9789241501361_eng.pdf Page 16
Clinical evaluation

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 Some Documents
– There is a wealth of information and processes in this area
– These slides were created from synthesising the information from the
following documents:
– https://www.tga.gov.au/sites/default/files/australian-clinical-trial-
handbook.pdf
– https://www.tga.gov.au/sites/default/files/devices-forms-essential-
principles-checklist.pdf
– https://www.nhmrc.gov.au/about-us/resources/ethical-considerations-
quality-assurance-and-evaluation-activities
– https://www.tga.gov.au/sites/default/files/clinical-evidence-guidelines-
medical-devices.pdf
– https://www.wslhd.health.nsw.gov.au/Education-Portal/WSLHD-
Research/ethics-governance
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 TGA Clinical Trials – Medicines and Biologicals
• Human pharmacology (micro-dosing)
• 10-15 participants
Phase 0 • Assess pharmacokinetics – preliminary data to determine drug behavior is as expected

• Human pharmacology
• 10-100 participants
Phase I • Safety and tolerance – different dosing, metabolism, and drug interactions

• Therapeutic exploratory
• 100-300 participants
Phase II • Efficacy and safety – IIa: demonstrate efficacy and explore dose range; IIb: resolve uncertainties, determine optimum therapy dose and regimen

• Therapeutic confirmatory
• 300-3000 participants
• Safety, efficacy, or effectiveness – IIIa: therapeutic effect in intended population, definitive assessment of risk-benefit assessment; IIIb: increase patient exposure
Phase III and support marketing claims and publication

• Therapeutic use
• Potentially many 1000s of participants
Phase IV • Post market surveillance or resolution of treatment uncertainties – monitoring safety in real world populations and refining knowledge, getting long-term data

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 TGA Clinical Trials – Medical Devices
• 10-30 participants
• Exploratory investigations to determine preliminary safety and performance information to plan
Pre-market design modificationsor provide support for a future pivotal study
pilot • Includes first in human, feasibility studies, or proofs of concept

• 100s of participants
• Confirmatory investigations to evaluate performance and safety for a specified intended use to
Pre-market satisfy pre-market regulatory requirements
pivotal

• 1000s of participants
• Confirmatory investigations to establish performance and safety in broader populations
• Observational investigations or surveillance to gain better understanding of device safety, long-
Post-market term outcomes, health economics

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 Early Phase Trials
– Now different to Phase I trials
– May include first in human studies
– Pose the greatest risk
– Greatest element of uncertainty in relation to risk
– Many clinical and non-clinical guidelines that may need to be
considered
– Incorporating findings following incidents from overseas clinical trials to
manage risk posed
– Human Research Ethics Committee (HREC) needs individuals with
appropriate expertise

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 More on medical device stages
– Often subject to extensive preclinical engineering analysis and testing –
sometimes animal testing
– Invasive devices often precluded from testing in healthy volunteers
– Considerations:
– Changes in material or design or new clinical indications require studies to confirm
performance and safety
– Safety and performance may depend on experience of person using the device
– Implantable devices – surgery to implant, and surgery to remove if failure occurs
– Essential Principles set out safety and performance characteristics
– Evidence from trial needed to demonstrate manufacturer has validated design
– Objective evidence required to substantiate compliance with Essential Principles

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 Essential Principles Checklist
– 20 pages of
this
– Required to
provide
evidence
– Or justify why
compliance is
not necessary
– There is
flexibility

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 Essential Principles Checklist
General:
– Principle One: Use not to compromise health and
safety
– Principle Two: Design and construction to conform
with safety principles
– Principle Three: Must perform the way the
manufacturer intended
– Principle Four: Must be designed and
manufactured for long-term safety
– Principle Five: Must not be adversely affected by
transport or storage
– Principle Six: Benefits must outweigh undesirable
effects
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Specific:
Principle Seven: Chemical, physical and biological
properties
Principle Eight: Infection and microbial contamination
Principle Nine: Construction and environmental
properties
Principle Ten: Principles for devices with a measuring
function
Principle Eleven: Protection against radiation
Principle Twelve: Medical devices connected to or
equipped with an energy source
Principle Thirteen: Information to be provided with a
medical device
Principle Fourteen: Clinical evidence
Principle Fifteen applies to IVDs only.
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 Clinical Evidence

“Every medical device requires clinical evidence, appropriate for the

use and classification of the device, demonstrating that the device
complies with the applicable provisions of the Essential Principles.”

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 Clinical Investigation Data

documentation in relation to the design, approval, conduct and results

of each investigation carried out by the manufacturer of the device in
relation to the use of the device in or on a human body; and

a record of qualitative or quantitative information obtained through

observation, measurement, tests or any other means used to assess the
operation of the device; and

a written report by an expert in the relevant field, being a report that

contains a critical evaluation of all the clinical investigation data held in
relation to the device

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 Evaluation of Clinical Data
Tool Applicable study designs Source
Jadad Score Randomised studies https://www.ncbi.nlm.nih.gov/pubmed
/8721797
Downs & Black Randomised & nonrandomised http://www.ncbi.nlm.nih.gov/pmc/arti
studies cles/PMC1756728/
QUADAS Studies of diagnostic accuracy http://www.bris.ac.uk/quadas/
AMSTAR Systematic reviews http://amstar.ca/

– TGA guidelines include list of inadequate types of evaluations

or data analyses

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 Manufacturing Guidance for Medical Devices
– No specific requirements
other than those for Essential
Principles
– Generally, manufacture is
regulated by:
– ISO 13485
– Certification by
independent third party
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– Start-ups many not have
certification
– Expectation of preparation
for certification
– Record keeping in
conformance with standard
– Trial sponsors should obtain
evidence to substantiate
compliance
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 Technical documentation
– Manufacturing records
– A technical file or device dossier (medical device file):
– a general description of the medical device
– the intended purpose of the medical device
– drawings of the design of the medical device, including components, subassemblies
or circuits
– descriptions or explanations that are necessary to understand the drawings of the
medical device and its intended purpose
– design calculations, risk analyses and technical tests or any other investigations
carried out on the medical device to establish compliance with the relevant Essential
Principles
– where the medical device is to be used in conjunction with (for example, connected
to) other medical devices, results of tests demonstrating the safety and performance
of each medical device is acceptable
– details of any standards used in relation to the manufacture of the medical device
– …

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Ethical considerations

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 Ethical Conduct in Human Research

– Evidence is a fundamental requirement

– Clinical trials and other such pilots are
research
– Where there are human
participants/subjects, ethical treatment
needs to be considered

– Similar category for animal research

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 Looking deeper into ethics
– The principles of right and wrong that individuals use to make
choices that guide their behaviour
– Responsibility – acceptance of consequences for
choices/decisions
– Accountability – determination of who is responsible for what
– Liability – legal responsibility for damages and consequences

Legal ≠ Ethical

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 Perspectives
– Common morality: set of moral ideals shared by most members
of a society or culture

– Personal ethics: set of one’s own ethical ideals, usually acquired

in early home or religious training and often modified or
shaped by individual experiences and reflections

– Professional ethics: set of standards adopted by professionals

for when they are acting in an official professional capacity

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 Review Application Process

Western Sydney LHD http://www.wslhd.health.nsw.gov.au/Research---Education/ResNet/ResApprProcesses

RG = Research Governance; RGO = RG Officer; CE = Chief Exec; SAC = Scientific Advisory Committee
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 Scientific Advisory Committee (SAC)
– Review all research proposals
– Responsibility and expertise for reviewing studies /clinical trials (with
respect to scientific rationale, study design, toxicology,
pharmacology)
– Ensure that the expected benefits to participants outweigh the
possible side effects.
– Studies involving devices may also be reviewed by the Biomedical
Department.
– On completion of the review and when SAC has no further concerns,
it then forwards their recommendations to the HREC for ethical
consideration

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 Human Research Ethics Committee (HREC)

gender balanced
chair
current community
experience in pastoral role lawyer
(min. 1) laypeople
knowledge of professional or religious (min. 2)
areas of care minister
research (min. 1) (min. 1)
(min. 2)

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may not be familiar with exact technology and its benefits
 Protecting Participants
Health and safety

Just because they are part of the trial doesn’t

Identity and privacy mean their identity can freely be made public

Bio-specimen preservation and destruction

Data preservation and destruction

Security

Ethically defensible plan if data needs to be returned

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 Different Types of Ethics Applications
– Influencing factors
– Type of study
– Level of risk
– Also governance reviews
– Framework for accountability
– Site-specific considerations
– Multi-site studies may become complex very quickly!

– Examples that may not require ethical approval are:

– Laboratory QA programs where no identifying information is recorded
– Anonymous and voluntary patients satisfaction questionnaires
– Statistical summaries of hospital activities

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 Quality Assurance (Audits)
– Sometimes conducted for quality improvement purposes
– Sometimes conducted to ensure things are working as expected
– Important for health services and care delivery
– Ethical considerations required if:
– Research involves a direct approach to patients or staff
– Personally or culturally sensitive information is to be collected
Consent is to be sought
– Individuals (or groups) could be disadvantaged as a result of participation
– Medical or electronic records of groups of patients are to be accessed
– Information collected could have ethical, legal or commercial implications
– Identifying information is to be collected
– The results might be submitted for publication
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 Negligible Risk
– No foreseeable risk of harm or discomfort
– Any foreseeable risk is no more than an inconvenience
– Filling in a form
– Participating in an anonymous survey
– Spending time to participate in a research study

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 Low Risk
– Only foreseeable risk is one of discomfort
– Minor side-effects of medicine
– Discomfort during blood pressure measurement
– Anxiety induced by an interview

– Determination of level of risk and appropriate level of review

is defined in a National Statement

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 Greater than Low Risk
– Fully funded sponsored
clinical trials of drugs or
devices
– Investigator-initiated studies
– Biomedical (laboratory)
studies
– Student projects
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– Can include:
– Clinical (all disciplines including
Dentistry)
– Basic Biomedical / Laboratory
research
– Nursing and Allied Health
– Mental Health
– Public Health and Epidemiological
– Health Services
– Psychological and Behavioural
– Social Science
– Qualitative (using questionnaires,
surveys, focus groups)
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 Single-site vs Multi-site
– NSW Ministry of Health’s Model for Single Ethical & Scientific
Review of Multi-Centre Research
– Accredited HRECs can be lead site for multi-centre research being
undertaken in NSW public health organisations.
– Mutual acceptance between New South Wales, Queensland
and Victoria (for clinical trials only)
– Introduction of the NHMRC’s Harmonisation of Multi-Centre
Ethical Review (HoMER)

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 Site-Specific Assessments
– Part of the research governance process
– Means that there are processes in place to ensure accountability,
transparency, inclusiveness, equity, responsiveness, etc.

– Often cannot commence a project at a site or any other site

until authorisation provided by the Chief Executive or their
delegate
– If processes are not in place then limited control over what is going on

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 Types of Harm to Consider
Types of harm Possible examples
Physical Harm Including injury, illness, pain
Psychological Harm Including feelings of worthlessness, distress, guilt, anger or fear related,
for example, to disclosure of sensitive or embarrassing information, or
learning about a genetic possibility of developing an untreatable disease

Devaluation of personal worth
Social Harms
Including being humiliated, manipulated or in other ways treated
disrespectfully or unjustly
Including damage to social networks or relationships with others;
discrimination in access to benefits, services, employment or insurance;
social stigmatisation, findings of previously unknown paternity status,
reputational harm to a participant, researcher, institution or community

Economic harms Including the imposition of direct or indirect costs on participants

Legal harms Including discovery and prosecution of criminal conduct
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 The Risk Matrix
– Used to assess risk rating
– Accounts for severity and likelihood
– Rank severity and likelihood separately from low (1) to high (5)
– Risk rating is the product of these two values
– Higher numbers represent modes of failure with higher risks

Frequent (5) 5 10 15 20 25
Likelihood

Probable (4) 4 8 12 16 20
Occasional (3) 3 6 9 12 15
Remote (2) 2 4 6 8 10
Improbable (1) 1 2 3 4 5
Minor (1) Negligible (2) Marginal (3) Critical (4) Catastrophic (5)
Risk Rating = Severity x Likelihood
Severity

How would these impact your design if taken to a clinical trial?

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Workshop

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 Weeks 2–5
– You will be working on the Formulation part of the project
– Defining the clinical problem
– Identifying areas where you need to conduct research
– Preliminary research
– Expanding requirements
– Brainstorming ideas to work on

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End

Remember to prepare for Week 4!

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