Ethical Review of Research: An Introduction

REalistiC
Decisions
an introduction to the
ethical review of research
To orientate yourself please read the next four slides, 2, 3 4 and 5.
suggestions for improvement and comments to hughtdavies@gmail.com
This presentation is designed to provide general information only. Our website Terms and
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Working in
committee
Purpose
of RECs and
regulatory
framework
Ethical
principles in
research
Research
methodology
QUADRANT 1
Working with other
committee members,
presenting our
views and listening
to others is key
to the success
of any REC.
QUADRANT 3
Ethical principles
underpinning
review.
QUADRANT 2.
Research regulation
is (increasingly)
complex! It’s
important we know
our own, and
others’, roles.
QUADRANT 4
Review must be
founded on a clear
understanding of the
context and method of
the proposal.
I’ve written this slide set to help new members of Research Ethics Committees in
the UK. It’s based on our induction programme and developed from a training
needs analysis of new and experienced committee members.
A description of this slide set

A short summary (16 slides)
1. Click here for a consideration of the place of research in health and health care.
2. Click here for practical guidance when starting on an REC.
3. Click here for what we ask REC members to do and not to do!
4. Click here for the purpose(s) and authority of RECs.
5. Click here for a guide to the UK regulatory framework for research.
6. Click here for the timelines of review in the UK.
7. Click here for an introduction to REC procedures when reviewing research.
8. Click here for an introduction to the Integrated Research Application System (IRAS) and the Participant
Information Sheet and considerations on the ethical domains of research
9. Click here for ideas on how to start review
10. Click here for a framework that might help review research.
11. Click here for introductions to quantitative and qualitative research methods
12. Click here for review of particular studies.
13. Click here for an introduction to the phases of modern drug development.
14. Click here for a picture of “Fair review”.
15. Click here for “How do we best review research to protect participants and patients?”
16. Click here for how to handle disagreements.
17. Click here for some guidance on “Law, Ethics and the REC”.
18. Click here for some questions and cases to consider.
19. Click here if you’re stuck!
20. Click here for the some suggested references / resources / e-learning.
Index
See what your
predecessors (past
new REC members)
have said

I would like……..
SLIDE
Integrated Research Application system guidance
Framework for review
Law and the REC - guidance Slide 298
Lead reviewer guidance Slide 66
Place of research in healthcare Slide 6
Practical example to test my knowledge Slide 378
Resources for further reading
Timelines of review
Some sections are
still under
construction or
being repaired!

There is a large amount of material in this slide set but I hope it doesn’t
frighten you. There's a short summary here, what to do if you’re stuck (here)
and I hope it’s easy to get around.
Its divided into 20 sections, listed in the index (next slide). You can click on any you
wish to chose. The slide after that is a task orientated list called “I would like to….”
Many slides are linked, indicated by “Click here”, underlined text in blue or a box
(however big) like this, clicking over it will take you on to a linked
slide. There will then be a similar box link back on that or a later slide.
You can also use the “Find” function to look for specific words.
The “Slide sorter” function in PowerPoint lays the slides out so you can view larger
groups.
If you get lost just find a slide with “Back to Index”
or “Back to beginning of section” at the bottom!
How to get around this slide set

The place of
research in health
and health care
Back to index

Learning from history
Those who don’t study history are destined to repeat
it. Those who do, are destined to stand by helplessly
while everyone else repeats it.
Research, health and history

Two centuries ago we didn’t live that long (unless
we were lucky). Improvements in our
understanding of health and illness, built on
research, have changed this.
David Wootton has written in his book “Bad
Medicine” that doctors only stopped killing their
patients when they researched their treatments to
find out which worked (and why).
“effective medicine could only begin when doctors
began to count and to compare” .
Research has improved health
TestingTreatments
Back to index

26 September, 2015
If you speak the truth, you Schoolmen....
Let us take..200 or 500 poor people with
fevers, pleurisy etc. and divide them in two:
let us cast lots so that one half of them fall to
me and the other half to you. I shall cure
them without blood-letting or perceptible
purging, you will do so according to your
knowledge
We shall see how many funerals each of us
will have: the outcome of the contest shall be
the reward of 300 florins deposited by each of
us.
1648
Research and health
Back to index

26 September, 2015
In December 1721, during an epidemic of
smallpox, Thomas Nettleton began to use
variolation to offer protection. However, there
was uncertainty and hostile and heated
debate about whether it did more good than
harm. To address this uncertainty, Nettleton
collected statistics on the mortality associated
with naturally-acquired smallpox and
compared these with mortality following
variolation.
Research and health
Back to index

26 September, 2015
Mesmerism
During a meeting of the faculté de Médecine,
Paris on 18th September 1780, a delegate,
Charles Deslon proposed a trial of
Mesmerism but this was roundly rejected by
the Faculté.
Research and health
Back to index

26 September, 2015
120 citizens of Nuremberg met in a local
tavern. 100 vials were split up at random into
two lots of 50. One lot was filled with distilled
snow water, the other with ordinary salt in a
homeopathic C30-dilution of distilled snow
water. These were given to volunteers.
Responses were obtained from 50 of the 54
participants.
8 out of the 50 participants had experienced
something unusual. 5 had received the
dilution, 3 had received melted snow.
The
Nuremberg
SALT
trials.
1835
Research and health
Back to index

26 September, 2015
Dr Spock recommended that babies should
be placed on the stomachs to sleep.
We didn’t ask “Where is your evidence?”
1950s
Research and health
Back to index

26 September, 2015
Bringing things up to date.
Improving treatment of head injuries
1999
Research and health
Back to index

In the past some research has harmed so now any medical
research proposal must undergo independent scrutiny by a
Research Ethics Committee (REC) to
• promote trust. People see research, which may depart
from standard care or involve extra interventions, as
distinct and have reservations about participating.
• protect. There are historical examples of harm to
participants.
• manage competing interests. The interest of the
researcher, the clinician and the patient or participant
may conflict.
• facilitate and promote good research for health benefit.
Research and harm
This was one of the
early requirements
of the World
Medical
Association’s
Declaration of
Helsinki
Testing Treatments
Interactive

Our Health Research Authority (HRA) was established in
December 2011 to protect and promote the interests of
patients and the public in health research, and to
streamline the regulation of research.

2015
What have we learnt,
what should we change?
History can only be a guide.
26 September, 2015
Research and health

My conclusion
26/09/2015
RESEARCH
US
Drink responsibly
Back to index

Research review:
practical guidance
Back to index

Practical guidance
Your committee is…………..
Your manager is ...................
Your Chair is .....................................
Your mentor or buddy ……………..…
Members……….
Claiming expenses…….
It meets
• Date and time ………………..
• Venue ……………
• Map and access ……….

Practical guidance
Has this happened?..................
PRE- START CHECKLIST
An appointment letter has been sent to the member with copy of
Terms and Condition, Declarations of Interest and a State Benefit
form.
Manager/Chair have contacted member to introduce themselves.
Mentor for new member has been identified.
The member has been sent a map to the meeting venue
List of meeting dates has been sent to member
Athens account has been set up
Member has been sent dates of next HRA induction days.
The member is given copy of expenses policy and an explanation of
the extranet and where information about training can be found
Equality and Diversity Training (as soon as possible after starting)

It might help break
up your training
needs into four
quadrants
QUADRANT 1
Working with other
committee members,
presenting our views
and listening to others
is key to the success
of any REC.
QUADRANT 3
Ethical (and other)
principles underpin
analysis of research
and judgements we
make.
QUADRANT 2
Research regulation is
(increasingly)
complex! It’s important
we know our own
roles and what others
do.
QUADRANT 4
Ethical analysis must
be founded on a clear
understanding of the
context and science
of a proposal.
Practical guidance

Research review:
purpose and
authority of RECs
Back to index

“A research ethics committee is a
group of people appointed to review
research proposals and decide whether
to give a favourable opinion. This means
the research must conform to recognised
standards, which include respecting the
dignity, rights, safety and well-being of
the people who take part while also
accommodating the interests of public
and patients.”
Governance Arrangements for
Research Ethics Committees
Purpose and authority of RECs (1 of 4)

Later on you might look at
http://www.testingtreatments.org
The central importance of
public trust in research:
independent review is one
way to promote this.
Why do we have RECs?
• To promote trust: people see research,
which may depart from standard care or
involve extra interventions, as distinct and
have reservations about participating.
• To protect: there are historical examples
of harm to participants.
• To manage competing interests: the
interest of the researcher, the clinician and
the patient or participant may conflict.
• To facilitate: to promote good research

So we ask you:-
“Is this a fair research proposal to
offer to people?”
“Researchers must satisfy a research
ethics committee that the research they
propose will be ethical and worthwhile.
The committee has to be assured that
any anticipated risks, burdens or
intrusions will be minimised for the
people taking part in the research and
are justified by the expected benefits for
the participants or for science and
society.”

The REC’s authority derives from
international guidance such as the World
Medical Association’s Declaration of
Helsinki, European and national law and
professional regulations.
These all require independent review of
research involving human subjects
Updated to
2013
version
Declaration of Helsinki
15. The research protocol must
be submitted for consideration,
comment, guidance and approval
to a research ethics committee
before the study begins. This
committee must be independent
of the researcher, the sponsor
and any other undue influence.

The UK regulatory
framework
Back to index

Health Research
Authority and
National Research
Ethics Service
(London) and
devolved authorities
(Scotland, Wales
and Northern
Ireland)
Your
REC
Regional offices (London,
Manchester,
Nottingham, Bristol,
Newcastle),
In the Devolved Nations there are
administrative and some legal differences
but we try to provide a harmonised
service. Seek advice if necessary
The regulatory framework

Who’s involved and what are their responsibilities?
The researcher’s roles:-
• Developing proposals that are scientifically sound and ethical.
• Submitting the study for independent peer review.
• Submitting the study for independent ethical review.
• Conducting a study to the agreed protocol (or proposal), in accordance with
legal requirements, guidance and accepted standards of good practice.
• Preparing and providing information for participants.
• Ensuring participants’ welfare while in the study.
• Arranging to make findings and data accessible after the study
• Feeding back results of research to participants.

The funder’s roles:-
• Assessing the scientific quality of the research as proposed.
• Establishing the value for money of the research as proposed.
• Considering the suitability of the research environment in which
the research will be undertaken, particularly the experience and
expertise of the chief investigator, principal investigator(s) and
other key researchers involved.
• Requiring that a sponsor takes on responsibility before the
research begins.

The sponsor’s roles:-
• Responsibility for putting and keeping in place arrangements to initiate,
manage and fund the study.
• Ensuring the research protocol, research team and research environment
have passed appropriate scientific quality assurance.
• Ensuring itself the study has ethical approval before it begins along with
trial authorisation and making appropriate arrangements for Clinical Trials
of Investigational Medicinal Products (CTIMPs).
• Ensuring that arrangements are kept in place for good practice in
conducting the study, and for monitoring and reporting, including prompt
reporting of suspected unexpected serious adverse events or reactions.

NHS Trust Research and Development Offices roles:-
• Ensuring the (approved) protocol can be implemented and fits the
organisation’s strategy
• Ensuring facilities and resources are adequate
• Ensuring the investigator and team are appropriately trained
• Ensuring costs for a trial agreed and contract in place
• Ongoing oversight is agreed and in place

Medicines and Healthcare Products Regulatory Agency (MHRA)
Medicinal products need to have a marketing authorisation before they can
be given to patients. This authorisation is based upon clinical trials of the
investigational medicinal product (you will hear the acronym CTIMPs),
undertaken to collect safety and efficacy data. These trials are conducted
under European and national legislation and the MHRA is our lead
“Competent Authority”. The Clinical Trials Unit is part of the Licensing
Division of the Medicines branch of the MHRA. The role of the Unit is to
assess applications from sponsors to conduct clinical trials with medicinal
products. It determines whether the product and proposed research are a
“CTIMP” and assesses the safety, effectiveness and quality of data to
justify any trial. Throughout the trial the MHRA has responsibility for
monitoring.

The Review of
Particular Studies

Clinical Trials of Investigational Medicinal Products (CTIMPs). (Medicine
research)
Here is a summary of key differences.
a. This research is conducted under specific legislation – Medicines for
Human Use (Clinical Trials) Regulations 2004. Whether a study is a
“CTIMP” is the role of the MHRA
b. The same processes apply in all UK nations.
c. The Medicines and Health Care Products Regulatory Authority (MHRA) is
the lead authority and is responsible for assessing the safety (toxicology)
of the medicinal product. The MHRA also monitors the studies.
d. Studies may undergo parallel review.
e. When there are differences in opinion it is possible for your chair to liaise
between your REC and the MHRA under our “Memorandum of
Understanding”.
Particular studies

Research with no material ethical issues
If research is deemed to have “No material ethical
issues”
http://www.hra.nhs.uk/resources/applying-to-
recs/nhs-rec-proportionate-review-service/
it may be reviewed by the Proportionate Review
service which is made up of a sub-committee of 3
members. Applications are reviewed within 14 days
(as opposed to 60 days for a full review). We won’t
expect new members to undertake this work early
on.
Particular studies
“NoMEIs”

Research involving those who lack capacity
Some committees are flagged to review this type of research. Briefly:
if, for any reason, subjects may lack capacity, researchers and RECs are
required to follow legislation (In Scotland the Adult with Incapacity Act and
in England and Wales the Mental Capacity Act). The IRAS form is
designed to provide you with the information you need and you would
also receive an MCA (Mental Capacity Act) checklist to help you review
the study.
If the research is a Clinical Trial (CTIMP) then the Medicines for Human
Use (Clinical Trials) Regulations 2004 apply throughout the UK. These are
broadly similar to legislation above but there are one or two minor
differences.
Your other committee members can help you to start . Further training is
available – see www.hra.nhs.uk and click on “Training”.
You could also look at our consent guidance
http://www.hra-decisiontools.org.uk/consent
Particular studies

Research using human samples or tissue
In England and Wales, if the samples have cells, the legal framework is
provided by the Human Tissue Act. We provide further training on this.
http://www.hra.nhs.uk/hra-training/training/
Research using personal data without consent
In these cases the researchers need favourable opinion from an REC and the
Confidentiality Advisory Group if the project is to be conducted in England or
Wales. Alternative arrangements are in place in Scotland.
We provide further training, http://www.hra.nhs.uk/hra-training/training/.
Particular studies

Discovery
Research
Pre-clinical
Development
Clinical Development Regulatory
Review
Post Marketing
Development
Phase I Phase II Phase III Phase IV
0 3 91 2 4 5 6 7 8 10 11 12 13Time (years)
Basic research
to understand
disease
Synthesis Biological
testing and
pharmacological
screening
Animal studies Long-term animal studies
Chemical & Pharmaceutical Development
Patent CTA MA
application
Mkt
Launch
Current drug development

The Preclinical Stage
Here biologists identify a biological target associated with the disease or
condition to be treated and develop experimental methods for determining
the ability of chemical compounds to interact with this target. The first of
these are usually “test tube” methods using single proteins, cell fragments
or whole cells. They then progress to studies in whole animals to see if
activity is maintained although only for very few diseases or conditions is
there a suitable animal “parallel”.
Then the identified compound, the IMP, moves into the first regulated
phase of development. The toxicity of the IMP is assessed in two species,
usually rat and dog to define safe limits of dose and blood concentration
that can be applied to humans. The toxicity on genes is also assessed..

Phase 1
In most cases the first administration of an IMP will be to healthy,
usually male, volunteers. Patients are only used at this stage if the
mechanism of action of the IMP is such that when considering the
risk/benefit equation it is not considered safe to dose volunteers. This is
the case with some, but not all, types of anti-cancer IMPs. The aim of
these studies is to establish the safety, tolerability and pharmacokinetics
of the IMP.
There are many other studies done in healthy volunteers to answer a
variety of questions (see section on Phase 1 CTIMPs) but this “First
time in Human” study is the key one that allows the development
process to proceed, or stops it in its tracks.

Phase 2, Exploratory Therapeutics
The aim in Phase 2 is to see if the IMP works at safe and tolerable doses and
if so at what dose should it be used in Phase 3. This is the first time the drug
is administered to patients. Phase 2 can be divided into 2a, which asks the
question does it work and is it safe and uses a single high dose level defined
by what is safe in Phase 1 followed by 2b in which several dose levels are
used with the intent of defining a dose response curve and establishing the
most suitable dose for Phase 3.

Phase 3, Confirmatory Therapeutics
Phase 3 trials should only be undertaken if there is evidence that the new
drug has adequate efficacy and that in the context of this efficacy the adverse
event profile is acceptable. The outcome of these trials will form the basis of
the filing of an application to market the drug. Such studies are large, many
hundreds or even thousands of patients lasting from a few days to a year or
more. These studies are often not just multi-centre studies but international in
their scope. They may be placebo controlled but increasingly a comparator
drug is included where possible and studies are designed to show that the
drug being studied is superior to, or more often not inferior to, the comparator.
Thus study design and statistical power, and hence patient numbers, are
critical.

Phase 4, Post Marketing Studies
These are studies carried out after a licence has been obtained. The
regulatory authority may, as part of the approval process, mandate such
studies putting restrictions on the type of patient who may be prescribed the
medicine until a specific phase 4 study has been done.
Developers often initially seek approval for a relatively limited patient
population or for one of a series of conditions for which the medicine may be
effective and must therefore carry out further trials to expand the therapeutic
scope of the product. Increasing emphasis is being placed on long term
clinical outcomes, looking at disease progression or at the effects on
mortality rates in the patient population. Such studies inevitably are very long,
involve many thousands of patients and are extremely costly and as such can
only reasonably be carried out once the product has been licensed.

Research review:
procedures and
processes

The process of review
Research Ethics Committees are established to
review the ethical dimensions of research.
Governance Arrangements for Research Ethics
Committees (GAfREC) is a key document for UK
RECs. (Click on the picture). It outlines how it should
discharge its responsibility
“Researchers must satisfy a research ethics
committee that the research they propose will be
ethical and worthwhile. The committee has to be
assured that any anticipated risks, burdens or
intrusions will be minimised for the people taking part
in the research and are justified by the expected
benefits for the participants or for science and
society.”

On an REC you have authority to review
and judge research. This derives from
international guidance such as the World
Medical Association’s Declaration of
Helsinki, European and national law (UK
Clinical Trial Regulations) and
professional regulations.
Declaration of Helsinki
15. The research protocol must be submitted
for consideration, comment, guidance and
approval to a research ethics committee
before the study begins. This committee must
be independent of the researcher, the sponsor
and any other undue influence. It must take
into consideration the laws and regulations of
the country or countries in which the research
is to be performed as well as applicable
international norms and standards but these
must not be allowed to reduce or eliminate
any of the protections for research subjects
set forth in this Declaration. The committee
must have the right to monitor ongoing
studies. The researcher must provide
monitoring information to the committee,
especially information about any serious
adverse events.

The aspects of research project RECs are asked to look at are:-
•Relevance and value of the project
•Adequacy of peer review
•Risks and benefits
•Selection criteria
•Inclusion of minors or adults
lacking capacity
•Approach to potential participants
•Information sheets and consent
forms
•Consent process
•Notifying other professionals
•Rewards/payments to subjects
•Chief Investigator and sponsorship
•Conflicts of interest
•Insurance, indemnity and
compensation
•Patient involvement, e.g. in trial
design
•Trial registration and publication of
results
All these are covered in sections of the research application form
called The Integrated Research Application System (IRAS for short)
http://www.myresearchproject.org.uk or the lead reviewer form (next slide)

HRA encourages RECs to appoint a lead review and provides this “Lead reviewer sheet”. It
lists domains as below:-
http://www.hra.nhs.uk/documents/2013/08/rec-review-best-practice-example.doc
• The suitability of the applicant and supporting staff
• The quality of the facilities
• The relevance of the research and research design
• Evaluation of anticipated benefits and risks for individual trial subject and patients
• Hazards, discomfort and distress of subjects
• Consent of the research subject, including justification for research on persons
incapable of giving consent
• The adequacy and completeness of written information to be given
• Recruitment arrangements
• Confidentiality,
• Indemnity and compensation
• General comments on the application

Research review:
what we ask you to
do (and not to do)
Back to index

What makes a good REC member?
How would you describe a
(i) Good
(ii) problematic
REC member?

What we ask you to do
Practically, and most importantly we ask you
to attend the requisite number of REC
meetings and in time help us with sub-
committee work and proportionate review.

TASK SKILL
To read the studies Commitment
To understand the content and context of the research Critical appraisal and imagination,
To consider all involved Empathy and respect
To identify and work out ethical problems Clarity of thought
To express opinions and judgements Clarity of thought and expression
To accommodate others’ opinions Listening, respect and humility
To weigh up arguments to make a decision Respect and humility
To accommodate disagreement Humility and confidence
To reflect on your convictions and values Insight

We ask you to help your chair and committee
manager.
Understand the chair’s job. He / she has to
• Manage fair debate
• Ensure all are heard
• Facilitate positive, friendly discussion with
researchers
• Bring the committee to a decision
Understand the manager’s job and think how you can
help. He / she has to
• Capture discussion
• Write a fair set of minutes
• Draft a letter for the researcher
BOTH have to ensure legal running of the REC
Henry Fonda in “Twelve Angry Men”
– a committee model? Click on the
picture and watch good and bad
behaviour!

Attack people personally Keep to the idea rather than
the person.
Agree with everything The purpose of the meeting is to
look at the application from different points of view.
Be inconsistent/changing the subject without
explanation It helps the chair and manager who have to
write minutes if items are addressed in turn.
Chat
Impose your views on others
Criticize (in a hostile manner) Comment on the idea not
the person!
Display anger
Display superiority/domination
Make a long-winded contribution Write down key points.
If you’re brief, you’re is more likely to be listened to!
What we ask you not to do

How should we work with researchers /
applicants?
There is continuing debate about this. A simple
model, with legal parallels, would be that the
researcher presents his project and the REC
decides, on the basis of the application and
perhaps discussion, whether it meets the required
ethical standards. Researcher and reviewer would
have no other intercourse.
But such a model may not best serve the
purposes of protecting research subjects and
facilitating ethical research. Time has
demonstrated that review works better when all
parties understand each other’s aims, their roles
and constraints, when they share ideas of what is
fair research and work together to facilitate this.

Being a (lead) reviewer
Be concise – assume committee
members have read the study.
Start with a short descriptive title using the
acronym I.P.C.O..
Define the research question.
Move on to the study as it would affect
someone who might join, a short description
of its burdens and consequences
Point out the key ethical issues as you see
them, aligning them with the answer to A6(ii)
the researcher's view on the ethical issues.
(avoid minute detail at the beginning).
Present your ideas but try NOT to bind
committee to their views
IPCO - what are
a) The Interventions (what
will happen to anyone who joins)?
b) The People being invited
to join?
c) The Comparator(s) (if it is
a comparative study)
d) The Outcome(s), purposes
and value?
Use the researcher’s answer to
A6(i) and A6(ii) to start (if they’re
adequate!).
Use our ethical review sheet

Step 1: Constructing a picture of the research
Two early questions that might help you
1.What EXACTLY is the research question?
2.What are
a) The Interventions (what will happen to
anyone who joins)?
b) The People being invited to join?
c) The Comparator(s) (if it is a comparative
study)
d) The Outcome(s)?
The project title, the
Participant
Information Sheet
(PIS) or the summary
(A6(i) in IRAS) are
good places to start.

Ground rules?
If you wanted ground rules for your committee to help review and
deliberation, what would you include?
What would be the advantages / disadvantages of drawing these up?
Ground Rules for RECs?

Past comments
from new REC
members
Back to index

What your predecessors have said
Key skills or capacities required of REC members identified at past meetings
1 Critical analysis of research.
2 Imagination and empathy
3 Presentation and skills of debate
4 Integrity and fairness / insight / open mindedness/ reflectivity / consistency
5 Interest, expertise and passion for research ethics
Problems
1 Building confidence
2 Finding time
3 Understanding technical language
4 Science and ethics – the role of RECs
5 Statistics
6 The law and ethical review
Back to index

Timelines for
research review in
the UK
Back to index

The next slide depicts timelines for REC research review in the UK.
Click over any text box for further explanation.
You’ll then be taken to a different slide.
To return to the timelines simply click on the slide.
More detail is in Health Research Authority
Standard Operating Procedures.
UK research review timelines

PROJECT
Dialogue
STUDY
END
UK research review timelines
Monitoring,
amendments,
adverse
events
Enter Integrated
Research
Application
System (IRAS)
Book a slot, submit application
form and paperwork
M
E
E
T
I
N
G
D
E
C
I
S
I
O
N
60 DAYS
Validation
Distribution
of papers
Notification
of final
decision
5 days 7-14 days
R.E.C.
Letter to
researcher
Researcher’s
response

This is the electronic gateway for researchers. When they wish REC review they must
complete the appropriate sections of “IRAS” and submit it electronically. The central
document you will receive is the application form, extracted from IRAS. (You’ll also receive
others such as a Participant Information Sheet)
It’s worth delving into this at some stage to familiarise yourself. Section “A” is the main “ethics
section”. There may be other sections depending on the nature of the research.
Ways you might explore IRAS
• Visit the “Help” section. Do the e-learning module.
• Create your own account and look through questions and “Question Specific Guidance”
(the little green “i” button”).
Links:
IRAS http://www.myresearchproject.org.uk.
“Help” section https://www.myresearchproject.org.uk/Help/HelpPage.aspx.
Content index: https://www.myresearchproject.org.uk/help/hlpirasindex.aspx.
Integrated Research Application System
Click in the box when you want to go back to the “Timeline”

This is an administrative check carried out by a REC Co-
ordinator to verify that an application is complete and may be
accepted for review.
Decisions on validation should be made within 5 working
days of receipt of an application.
Validation

The agenda and papers for committee meetings should
normally be distributed no later than 7 days prior to the
meeting.
Distribution of papers

The proper running of the
committee to ensure it meets
legal and policy requirements is
the responsibility of your
manager and chair.
You’re expected to attend
2/3rds of scheduled REC
meetings (with some
exceptions).
When considering a study, most
RECs appoint lead reviewers,
using a standard template. You
won’t be asked to do this at first.
The researcher is strongly
encouraged to attend.
information.
If you have interests in an
application you should declare
these at the beginning.
Before the researcher attends
•To hear the lead reviewer’s summary, to resolve
uncertainties so the REC has a shared, accurate picture.
•To put forward and listen to concerns and suggestions.
•To identify issues to discuss with the researcher along
with questions, suggestions and tentative remedies.
Discussion with the researcher
•To resolve remaining uncertainties, to listen to the
researchers’ summary of the ethics in the research, to put
forward committee concerns and listen to responses.
•(There is an undoubted subtext to review - the probity
and character of the researcher(s).)
After the researcher has left
•To review the discussion with the researcher
•To reach agreed judgments, decisions and remedies
•To consider the drafting of a letter to the researcher:
comments, agreements, requests and instructions.
•To vest authority in those who will follow up issues
REC meeting (1 of 2)

26 September, 2015
The aspects of research project RECs are asked to look at are:-
All these are covered in sections of the research application form
called The Integrated Research Application System (IRAS for short)
http://www.myresearchproject.org.uk
Its worthwhile looking into this web site as it is the key material you will receive.
•Relevance and value of trial
•Adequacy of peer review
•Risks and benefits
•Selection criteria
•Inclusion of minors or adults
lacking capacity
•Approach to potential
participants
•Information sheets and
consent forms
•Consent process
•Notifying other professionals
•Rewards/payments to subjects
•Chief Investigator and sponsorship
•Conflicts of interest
•Insurance, indemnity and
compensation
•Patient involvement, e.g. in trial
design
•Trial registration and publication of
results
•Protocol
REC meeting (2 of 2)

A REC should reach one of the following
decisions:
1. Favourable opinion
2. Favourable opinion with additional conditions
3. Unfavourable opinion
4. Provisional opinion with request for further
information, clarification or revision
5. Provisional opinion pending consultation with a
referee – a written request for information may
be made following receipt of the referee’s
advice
REC decisions

Where a REC requires further information before
confirming its opinion, it may give a provisional
opinion and make one written request for
further information, clarification or changes to
documentation such as the participant
information sheet. The clock stops until the REC
receives a complete response to the request.
The REC may ask for clarification but should not
raise new issues.
“Committees can only have
one bite of the cherry”
Terry Stacey former director
COREC
Dialogue

A final opinion is reached once the researcher’s
responses have been received and reviewed
(according to the conditions laid down by the
committee).
This opinion may be:
1. Favourable
2. Favourable with conditions*
3. Unfavourable
*These “conditions” can only be such that, if not
followed through, in essence wouldn't change the
REC’s opinion.
Final decision

Monitoring
The REC has a limited role in monitoring the study. Responsibilities lie elsewhere. However
the REC should receive an annual report.
Amendments
Some projects will require amendments after their start. These are classified as substantial or
minor, only the former need be reported to the REC and this classification is the responsibility
of the sponsor. The REC has 35 days from receipt of a valid notice of amendment to give an
opinion. The clock doesn’t stop during this period. Amendments may be reviewed in sub-
committee or at a full Committee meeting, but not by the Chair acting alone.
Adverse events.
Any adverse event that is serious and unexpected must be reported to the REC. These are
any event that (a) results in death, (b) is life-threatening, (c) requires hospitalisation or
prolongation of existing hospitalisation, (d) results in persistent or significant disability or
incapacity or (e) consists of a congenital anomaly or birth defect.
These are, by and large, confined to Clinical Trials of Medicinal Products (CTIMPs) and
therefore action lies with our Medicines and Health Care products Authority (MHRA).
Monitoring, amendments and adverse events

Final report
Once the study has ended (within a year), the main
REC should receive a final report. This should
contain information on whether the study achieved
its objectives, the main findings, and arrangements
for publication or dissemination of
the research including any feedback to participants.
This is reviewed by the chair or vice chair. It is at
his or her discretion whether it is reported to the
committee.
Study end
JOINING IN

60 days
Current REC statistics
Back to index

IRAS and the
Participant
Information Sheet
Back to index

IRAS and the process of review
It all starts with the paperwork!

Two key documents
Back to Index

This is the central system from which we construct the
application form you receive. When a researcher IN
THE U.K. wishes to submit a project for review, he or
she goes to http://www.myresearchproject.org.uk and
completes the form on line.
Have a look, you don’t need an account and you can do
the e-learning module or look at our question specific
advice attached to each question.
Ways you might explore IRAS
• Visit the “Help” section Do the e-learning module.
• Create an account and look through questions and
“Question Specific Guidance” (the little green “i”
button”).
• Go through the content index.

Some questions in IRAS you
might focus on when you
start
Two aims, Four steps, Eight questions

IRAS question Subject
A1 Title of research
A6 (i) and (ii) Study summary and possible ethical issues
A10-12 Principal research question / objective and justification
A13 Summary of the research method
A15-17 Who will be recruited, who will be excluded?
A18-20 Details of all procedures and what might be withheld
A22 Potential risks, burdens and benefits
A25 Arrangements after the research has finished
A27-29 How potential participants will be identified and how their data will be accessed
A30 Arrangements for consent
A36-45 How data will be handled and protected (confidentiality)
A46-48 Incentives and payments
A50-53 Registration, publication and dissemination
A54 Scientific critique
A76, 77 Insurance/indemnity - management of study
Back to beginning of IRAS section

What do you think would be the
ethical issues in the study:
“ A study interviewing and
examining victims of torture to
identify current techniques and
consequent physical sequelae,
to aid future medical
examinations.”?
Title
A well written title (not always provided!) will help
you work out much about the study
Using the acronym “P.I.C.O.” might help review.
• Population to be recruited
• Intervention
• (Comparator)
• Outcome
Likely issues that you’ll need to think about will then
emerge.
Back to list of questions

A6(i) and (ii): Summary and ethical issues
A6(i) is a 300 word summary written by the
applicant. If well constructed, it can provide a
description of the study (“Who, Where, Why,
When and How?”) that will help at the
beginning of review.
A6(ii) asks the applicant to summarise the
issues arising from the project and how they
will be handled. It can be a useful way to start
to identify challenging issues in the study.
Placebo?
Confidentiality?
Uncertainty?
Fair choice?

A10 to 12: Research question / objective
We suggest researchers pay particular attention to the
purpose of their research and the question it addresses.
“What, exactly, is the research question that this
project attempts to answer?” is always central to
review.
The purpose of some studies is to help the applicant
develop research expertise. This is perfectly acceptable
but can’t justify poor or unethical research.
Researchers should demonstrate they have reviewed
previous work and show how their study will add to
current knowledge.

A13: Summary of research method
In review it’s important to check that the method can, in
theory, answer the research question.
The answer to this question should include why the
study design and methodology have been chosen, what
has influenced the choice and how the chosen method
will answer the research question.
It will also be where the reviewer starts to consider what
the participant will have to do (and the consequent
burdens and risks).

“Sound method or good science” is important.
As a maxim, bad science is bad ethics. Poor science
endangers us all. If we look at past research
misadventure it’s clear that proper scientific review is one
of the most important parts of participant protection.
Consequently rigorous yet commensurate scientific
review is essential. In the UK, the applicant is expected
to submit scientific/peer review of his / her research
project. (RECs may ask for this but evidence is that they
don’t always feel this is necessary for their review. They
have enough information through IRAS.)

A research project should start with exploration and description
of prior knowledge on which it can build.
It should have purpose with a clear research question.
It should have a stated method described to enable repetition.
The research team should have, or have access to, the
required expertise.
Design, data and results should be open to scrutiny and
further use.

A13: Summary of research method:
“Responsible Research Practice”
1. What is the research question and is it of
clinical/scientific relevance?
2. Is the project built on what is known
already?
3. Will the method answer the research
question?
4. Are the research team equipped to
complete the study?
5. Are views of patients and participants
accommodated?
6. Are participants fairly recruited (justifiable
inclusion / exclusion)?
7.Have participants been offered a fair
choice? (Informed consent)?
8.Have consequences been fairly evaluated
and risks minimised?
9.Is personal data handled appropriately
(confidentiality)?
10.Once finished, will participants receive
appropriate care?
11.Will the project be registered and results
be in the public domain?

A15-17 Who will be included, who will
be excluded?
The reviewer needs to know who the
participants will be. Inclusion and
exclusion criteria may affect the
generalisability of the study and the
value of any results.
There can be fair and unfair reasons to
“include or exclude”. What’s important is
that they are not arbitrary.
Judgement is needed.
Fair Unfair
Inclusion
? ?
Exclusion
? ?

A15-17 Process of recruitment
Who is recruiting or approaching subjects? Were
the subjects’ details fairly obtained? If this is through
medical records, this should be a member of the
clinical care team. There should be “No surprise
contacts”.
What does the recruitment material (if any) say?
The purpose of study should be adequately and
honestly explained and any financial remuneration
should not represent undue influence.
Are the data collected at screening limited to the
needs of the study alone? The data collected at this
stage should be no more that that needed to go the
next step (consent).

A15-17 Process of recruitment
Should the subject‘s health care practitioner
(probably GP) be contacted to ensure there are no
medical contra indications?
If there may be health consequences the GP should be
contacted to ensure there are no reasons why the
subject shouldn't take part. Any relevant health care
professional should be informed if participation might
effect later treatment. Otherwise this is not mandatory. .
Are there plans to re-contact those who have not
replied?
Reasonable attempts should be permitted.
How will “Overvolunteering” be prevented in
research where subjects are paid?
http://www.TOPS.org.uk

A18-20: Details of all procedures and
what is withheld
These will clearly be central to review
in determining the consequences of
participation (benefits, burden and
risks).
A list or table, such as this, helps.
Research
procedures
Treatment or
tests withheld

A22: Potential risks, burdens and benefits
Our review must be efficient, commensurate
and fair so we must balance the undoubted
benefits of research and possible harm for
ALL parties involved. Research is a public
good and we can’t simply say that as
research has potential risk, we won’t approve
any. There is undoubted risk to doing no
research; unresearched care may be
dangerous. Our review is therefore a
complicated matrix, encompassing and
accommodating risk and benefit to all parties
- participants, patients and public.
BENEFIT
HARM

This should be a balanced consideration of benefits
in relations to risk and burden of joining the study,
with an explanation of what has been done to
minimise the effects. It helps if this is, as much as
possible, from the participants’ perspective.
Consultation with community or patient groups will
help.
?

The reviewers’ role (that all share) is to ensure
• risks are not excessive.
• risks are reduced or “minimized” and managed
appropriately.
• risks are no more than “minimal” when the research
offers no prospect of clinical benefit and informed
consent can’t be obtained.
• risks are reasonable in relation to the potential
clinical benefits for participants and/or the potential
social benefits of the research.
• participants adequately understand the balance of
benefits and risk of harms when they give consent.

Can the research be classified so likely benefits and
harms can be scaled?
Can a threshold or scale for research risks be identified
and applied?
Who has legitimate interests in this project?
In therapeutic trials, have consequences of the disease, of
the treatment and of the proposed research been
separated?
Have risk been minimised? Is there a management plan
for any remaining possible risks?
Have the consequences been analysed as potential
participants might see them?
Is the explanation of the consequences of participation
acceptable?

A25: Arrangements after
research has finished
Anyone who has been in a
research project should not be
“left in the lurch”.

A25: Arrangements after research has finished
Providing a public record of results
Ethical research is open research. Research is without
point if the results are hidden or distorted and hence
details of all trials (aborted, completed, successful,
unsuccessful, positive or negative) should be publically
accessible. Future researchers can learn from any of
these. Applicants, particularly those undertaking
therapeutic research, need to present a very cogent
counter argument if they don‘t intend to place their work
and its results in the public domain.
Providing results for trial participants
Aggregate or individualised results should be available to
those who wish. It will probably depend on the nature of
the study and resources available to the researchers.

A25: Arrangements after research has finished
Providing post trial access to treatments
Some argue that participants should receive any effective treatment
determined by the study, others that this is impractical and the
researchers’ only duty is to determine the facts of the matter, not to
provide treatment and any such demand would prevent research.
This is still unresolved. Expert opinion gives no definitive
guidance. What is clear is that, as a basic minimum, the
arrangements for post trial access need to be explained when
seeking consent.
http://jme.bmj.com/content/early/2013/05/04/medethics-2013-101398.full

A27-29: How potential participants will be
identified
The principle of “No surprises”: anyone
approached to be invited to join research should
not be surprised to receive the invitation! They
shouldn’t feel researchers have been intruding
into personal information which they have no right
of access.
Health records are personal, sensitive data and
should not be accessed without due authority. By
and large this should be done by the care team.
An ambush is a sort of
surprise.
“So is a gorse bush”
said Pooh!

A30: Arrangements for consent
For most research, consent is a legal and ethical
requirement. There are exceptions but these
need careful consideration.
For more detail see
http://www.hra-
decisiontools.org.uk/consent/

A30: Arrangements for consent
Fair consent needs
• time
• discussion and the opportunity to ask questions
• a fair question
• ongoing opportunity to re-consider when appropriate
Fair consent requires that those being asked can
• understand what the research involves (have capacity).
• understand the alternatives to taking part.
• retain the information long enough to make an effective decision.
• make a free choice., at the time it needs to be made.
Fair consent requires that those seeking consent can
• ensure the participant is able to decide for him or herself (capacity)
• judge and provide adequate information
• check understanding
• ensure they don’t exert undue influence.

A30: Arrangements for consent: considering capacity
Guidance supporting the Mental Capacity Act (2005 England and Wales) provides a
useful framework. Firstly, assume the person has capacity, do everything possible to
support the person make their own decision and be aware that a person has the right to
make an ‘unwise’ decision, although an ’unwise’ decision may be evidence of
incompetence. This requires judgement.
Ask
a. Does the person have an impairment of, or disturbance of the mind or brain
b. Does the impairment mean they are unable to make this particular decision?
A person is unable to make a decision if he is unable
a.to understand the information relevant to the decision
b.to retain that information
c. to weigh up that information to make a decision
d.to communicate his decision.
The burden of proving a person lacks capacity is on the person making the claim.
There is a need to demonstrate ‘reasonable belief’ of lack of capacity and record the
assessment process.

A36-45: How data will be handled and protected
The "Caldicott Principles" from “The Caldicott report
2013” set out an ethical framework.
• Justify the purpose(s) for obtaining the information.
• Don't use identifiable information unless absolutely
necessary.
• Use the minimum necessary person-identifiable
information.
• Access to identifiable information should be on a
strict need-to-know basis.
• Everyone with access to identifiable information
should be aware of their responsibilities.
• Understand and comply with the law.
• The duty to share information can be as important as
the duty to protect confidentiality.
Link to Caldicott

Generally speaking, participants should not be
out of pocket if they join a research project.
Reviewers needs to be reassured that any
payment beyond expenses will not be so
excessive as to act as undue influence.
Payment should not be based on risk incurred
(if any).

We could draw up 6 models for payment.
1.“Altruism”: The participant joins the study
without payment
2. Expenses / Reimbursement (the common
model in later research)
The participant is not out of pocket as a result of
participation
3. “Barter”: Participants receive access to health
care in return for participation.
4. Minimum wage : Payment is at the level of the
minimum wage .
5. Market (probably the predominant model in early
phase research). Payment is dictated by market
demands.
6. Wage replacement: Payment replaces wages.

A50-53: Registration, dissemination of
results
Research should be placed on a public register
at its outset. This is now a condition of
favourable REC opinion in UK for clinical trials
and encouraged for others).
To have any value, research results, positive or
negative, must be in the public domain. Access
or publication policies should be considered in
review and not be restrictive.
Consideration is also needed as to how results
will be provided for participants.

A54: Scientific critique
Research must be subjected to review by
independent* experts in the relevant fields prior to
submission.
This is one of the most important ways we
protect participants, patients and public.
*NOT those directly involved in the work those with
personal (pecuniary or non-pecuniary) benefit, close
friendship or family interest or those with close links.

A54: Scientific critique
Arrangements for review should be
commensurate with the scale of the research.
This should match the study’s burden.
It may be through:
i. Independent external review
ii. Review within a company
iii. Review within a multi-centre research group
iv. Review within the Chief Investigator's institution
or host organisation
v. Review within the research team
vi. Review by the educational supervisor

A76, 77: Insurance/indemnity
Appropriate arrangements should be in place in
case a research participant is harmed.
In “drug trials” this is usually covered by “no fault
compensation” provided according to guidelines
produced by the ABPI (Association of British
Pharmaceutical Industries).

Back to list of
questions

Participant Information Sheet
• A PIS should be written with the question
“What does participation mean for me (the
research participant)?” in mind.
• Its purpose is to help people make a choice
they will be happy with. They often want help;
influence is fair, coercion isn't.
• A PIS only one part of “consent” – evidence
indicates the most important part is the
discussion, which the PIS can support and
frame.
• “One size will not fit all types of research”.
• The benefits, harms and risks are central,
these need to be well described.
• The competence and training of those seeking
consent is central to fair consent.

• The language used should be no more
difficult than that used in common
newspapers.
• Diagrams or pictures can be used to clarify
issues.
• Informed consent and fair choice require
potential participants to be furnished with
benefits and harms. Closely attached should
be a table of what is extra in the research
and what is to be withheld.
• When appropriate, researchers should
consult possible participants in design.
• Many RECs simply ask members to provide
any minor comments in writing to save time.
Realistic review is needed.
Participant Information Sheet (contd)

Participant Information Sheet
Our guidance:
http://www.hra-decisiontools.org.uk/consent/
Back to beginning of IRAS section

A framework for
reviewing research
Back to index

This slide set describes a framework that
I hope will help you review research
proposals. But at the outset it’s important
to recognise that it can’t “make the
decisions” for you.
Its aim is to explore the foundations on
which you can build your decisions.
“The work of RECs is explicitly
one of judgement and discretion”
Dixon Woods 2007
Purpose of this slide set
Back to beginning of this section

?
Research review
I propose we can look at review as a
process with 2 aims, 4 steps and
decisions founded on 7 broad questions.

BENEFIT
HARM
Two aims of research review
The danger of
unresearched
health care for
babies
(i) Protect research participants (ii) Facilitate good
research
We must weigh up the benefits and harms for
participants (research consequences) but we must then
balance these against the possible harms of
unresearched health care (NOT doing the research) and
how research can benefit future patients. We need
research.
So our review is thus complicated. It has to encompass
and accommodate harm and benefit to many groups:
participants, patients and public.
More detail can be found in the website
http://www.testingtreatments.org

An example to consider

Should the age of breast screening be extended?
The benefit of screening for breast cancer in different
ages is uncertain so the Medical Research Council
has submitted a study entitled “Evaluating the effects
of extending the breast screening programme from
50-70 years (current practice) to 47-73 years” to your
REC. Women in the age groups (47-49 and 70-72)
will be randomly allocated to screening. Half will be
offered screening, half will not.
List the parties you think have an interest in this
study and what their concerns might be.

Should the age of breast screening be extended?
Participants
The consequences of
participating in this study
Women in these age
ranges
The possible benefits /
harms of such extension
Health planners and
government
Designing a rational
service
Other groups you can
think of?
Wider Public
Use of taxation:- the
financial cost and
effectiveness of this
programme

How can we improve this aspect of our review?
• Acknowledge this dual role of protection and facilitation.
• Try to identify all who might have an interest in the research.
• Recognise that our responsibilities to one group can not exclude those we
may have to others. We must balance these.
• Seek a realistic assessment of research consequences. Match these with
the value of this research in health care.

The next slide depicts four steps into which we could
break review (the left hand column), the question each
addresses (middle column) and the skills we need (right
hand column).
For further explanation click over any text box:-
You will then be taken to a different slide. To return to the
diagram go on to a slide with a and click
again on the slide.
Four steps of research review

Step 1 Construction
Drawing a picture of the
study to find out what it’s all
about.
Step 2 Deconstruction
Breaking the study down
into “research domains”
Step 3 Decisions and
“Seven questions”
Step 4 Working in
committee
What are the context and
content of the study?
Can I break this study
down into manageable
issues?
What gives rise to
concern?
Should it?
An individual view –
reaching committee
agreement.
Critical appraisal
Ordering and structuring
Moral imagination
Moral analysis
Collaborative
Working
Four steps
(click on the yellow boxes for more detail)
Steps Questions Skills

The end
Thank you for listening or reading.
Back to index

Factual errors or misconceptions are very
likely to lead to delay, ethical errors (and even
argument).
“I do not believe you can make moral
judgements unless, as far as possible, you
now what you are talking about”
Mary Warnock 1998

So when we start we need an overview of the
study. We need to
• “find out what it‘s all about”
• “determine the facts of the matter”

This process of “construction” also has a further
purpose. It helps identify key ethical issues that
will help review.
As an example, what are the likely ethical issues
in
“A randomised, placebo controlled trial of pufficillin
in children with Cystic Fibrosis assessing
response by lung function”?

How can we develop this aspect of our review?
• Careful reading of the application.
• Learning where to find relevant information (Title, PIS,
A6(i) in IRAS).
• Defining the research question and purpose
• Using the acronym “IPCO” (Intervention, Population,
(Comparator) and Outcome).
• Being willing to say “I don’t understand this” and asking
for help.
Click in the box when you want to go back

Step 2: Breaking a study into research domains
Step I, “Construction” doesn’t permit judgement, such a
picture will lack sufficient detail to allow full analysis. We need
to break the study into constituent “research domains”. Within
each we can then make judgments and reach our decisions.
2. After Emanuel et al (now the
REC lead reviewer proforma)
• Social or scientific value
• Scientific validity
• Fair subject selection
• Favourable risk benefit ratio
• Independent review
• Informed consent
• Respect for potential and
enrolled subjects
JAMA. 2000;283:2701-2711
What Makes Clinical Research Ethical?
* Integrated Research Application System (UK) www.myresearchproject.org.uk
1 Based on IRAS*
• Independent review
• Social and scientific value
• Suitability of applicant and support
• Recruitment, access to information
• Inclusion and exclusion .
• Risk, harms and benefits
• Consent and participant Information
• Confidentiality
• Payment to participants
• Compensation, insurance
• End of trial arrangements

How can we develop this aspect of our
review?
• Have a framework with which we’re
familiar and find easy to use.
• Use the “Study review sheet template”
Step 2: Breaking a study into research domains
Click in the box when you want to go back
Click here for the “Study review sheet template”

Application
Decision
Judgment
STEP 3: Judgements and decisions
Previous steps are only a means
to an end. Within each domain we
can identify issues and ask specific
questions to see what is proposed
but we can’t reach any judgement
and make a decision. This is the
purpose of Step 3, seven
questions….
Index

DECISION
6. ETHICAL THEORY
How would an ethical
analysis help?
5. EVIDENCE
What published
evidence is available?
7. EXPEDIENCY
What is possible and
realistic?
2. EMPATHY
How do I accommodate
views of all interested
parties?
3. EXPERTISE
What guidance is there from
expertise in committee, peer review
or external experts?
4. EXPERIENCE
What have I / we decided
before?
1. EGO
What’s my (“immediate”)
view?
ISSUE
Step 3: Decisions and 7 questions
Back to beginning of section

1. What’s my (“immediate”) view?
2. How might interested parties decide?
3. What expert guidance is there?
4. What have I / we decided before?
5. What published evidence is available?
6. How might ethical theory help?
7. What is possible and realistic?
Step 3: Decisions and 7 questions

Exploring an issue
How might this model work?
Considerations about fair use of placebo
26 September, 2015

Efficacy of Emesatide on Cisplatin induced nausea and vomiting in patients
undergoing chemotherapy for lung cancer
The study will compare a new drug Emesatide with placebo in 28 patients with cancer
due to receive cis-platin treatment (this treatment is VERY likely to make them vomit).
Patients will be randomly allocated 1 to 1 to receive either standard treatment plus
placebo or standard treatment plus Emesatide. Rescue treatment will be provided for
either group if treatment fails.
Robin, a committee member opens the discussion: “I think placebo is completely
unacceptable, I cant approve this study! I hope you’ll all agree.”
Noel: “Well I’m happy with this placebo arm.”
Question 1:
If you were chairing this meeting how would you handle this dispute?
Question 2 :
How would you explore this use of “placebo”?
Using placebo
Cubeddu LX Efficacy of odansetron and the role of serotonin in cisplatin
induced nausea and vomiting N Engl J Med 1990 322 81

Fair or unfair
6. ETHICAL THEORY
analysis help?
5. EVIDENCE
What published
7. EXPEDIENCY
realistic?
2. EMPATHY
How might “interested
parties” decide?
3. EXPERTISE
4. EXPERIENCE
before?
1. EGO
view?
Seven questions to help explore using placebo
Using placebo

1. EGO What’s my
(“immediate”) view?
When we need to make a decision we
often start by taking up a particular
stance, in favour or against a proposal.
It’s speedy and practical, particularity
when we’re busy or have many decisions
to make but it may present problems
when sharing a decision.
The foundations of our thinking may be
“undeclared” and closed to scrutiny.
Without further elucidation, debate and
shared decisions are impossible. If, in this
case, there are different views about
using placebo, any position should be
respected (within reason), but further
analysis is needed.
Using placebo
Blackburn’s “Staircase of
practical and emotional
ascent”
Immediate?
Considered?
Judgements
Preferences
Likes / dislikes
Tastes
Hostility
Disgust
Passions

We could describe this as going
beyond “putting ourselves in the
potential participants’ shoes”
rather “getting into their brains” to
empathise with their position.
2. EMPATHY How might the
participants decide?
Here other views (public, patients’ or
participants’ views) are our standard. As
an ideal accommodating these would
seem the best way to represent others in
our review.
What would those who might join the
project think about taking a placebo?
Has the research team consulted
potential participants? If so, what were
the results?
Using placebo

3. EXPERTISE What expert
guidance is there?
‘The World Medical Association hereby
reaffirms its position that extreme care must
be taken in making use of a placebo-
controlled trial.. However, a placebo-controlled
trial may be ethically acceptable, even if
proven therapy is available, under the
following circumstances:
i where for compelling and scientifically sound
methodological reasons its use is necessary
to determine the efficacy or safety of a
prophylactic, diagnostic or
therapeutic method; or
ii where a prophylactic, diagnostic or
therapeutic method is being investigated for a
minor condition and the patients who receive
placebo will not be subject to any additional
risk of serious or irreversible harm’
Using placebo
page 49

3. EXPERTISE What expert
guidance is there?
Emanuel EJ, Miller FG 2001 The
ethics of placebo-controlled trials--a
middle ground. N Engl J Med. 2001
Sep 20;345(12):915-9
Using placebo
Justifying placebo
• Is there a licensed or established treatment
which will be withheld?
• Is there uncertainty as to which (research
treatment or placebo) is better (also known as
“equipoise”)?
• Are there clear scientific reasons for using a
placebo?
• Could a trial without placebo answer the question
just as well?
• Would the risks of placebo be greater than the
standard of “minimal risk”?
• Will adverse consequences, if on the placebo, be
minor, transient and reversible?
• Will adverse events (“side effects”) be identified
and managed properly for all participants?
• Does the information provided explain clearly the
possibility that a participant may receive the
placebo?

4. EXPERIENCE What have I
/ we decided before?
What decisions have the REC made in
similar circumstances?
(It certainly would help subsequent
review if this dispute lead to
agreement on scales of payment).
Using placebo
What have
we decided
about
placebo
before?

5. EVIDENCE
What published evidence is available
about the acceptability of placebo?
Using placebo

6. ETHICAL THEORY(IES)
Consequentialism
Principle based ethics
• Beneficence
• Non-maleficence
• Respecting Autonomy
• Justice
These theories and principles don’t necessarily
agree with each other and reviewers will often
have to decide between them.
Using placebo
What do they say about
placebo use?
How can we sue them to
resolve differences?

7. EXPEDIENCY
What is possible and realistic?
The 1996 debate on placebo…..
Using placebo

Has this helped?
What other help might you offer REC
members?
Using placebo

To reach consensus we must have an accurate
picture of the research, put forward our views,
concerns and suggestions, listen to others. Then
we can suggest remedies and vest authority in
those who will follow up.
The REC meeting can be divided in three parts,
each with its own purposes:-
1. Before the researcher attends,
2. Discussion with the researcher,
3. After the researcher has left.
Step 4: Committee deliberation (1 of 4)

Before the researcher attends
•To hear the lead reviewer’s summary, to resolve uncertainties so
the REC has a shared, accurate picture.
•To put forward and listen to concerns and suggestions.
•To identify issues to discuss with the researcher along with
questions, suggestions and tentative remedies.
Discussion with the researcher
•To resolve remaining uncertainties, to listen to the researchers’
summary of the ethics in the research, to put forward committee
concerns and listen to responses.
•(There is an undoubted subtext to review - the probity and
character of the researcher.)
After the researcher has left
•To review the discussion with the researcher
•To reach agreed judgments, decisions and remedies
•To consider the drafting of a letter to the researcher: comments,
agreements, requests and instructions.
•To vest authority in those who will follow up issues

What does this mean for REC members?
To reach a shared decision we must
• Resolve uncertainties so we all have an
accurate picture of the research.
• Put forward our views, concerns and
suggestions.
• Listen to those of others.
• Reach agreed judgments, decisions and
remedies.
• Vest authority in those who will follow up
issues.
Task Skill
To read the studies Commitment
To understand the context of the
research
Critical appraisal
To consider all involved Empathy and
respect
To identify ethical problems in
the research
Clarity of thought
To express opinions and
judgments
Clarity of thought
and expression
To identify, understand, and
accommodate others’ opinions
Listening,
respect and
humility
To accept and weigh up
arguments to make a decision
Respect and
humility
To accommodate disagreement
but if necessary stand firm
Humility and
confidence
To identify and question our
own convictions and values
Insight

The end
Thank you for listening or reading.
Back to beginning of section Back to Index

DECISION
6. ETHICAL THEORY
analysis help?
5. EVIDENCE
What published
7. EXPEDIENCY
realistic?
2. EMPATHY
How might “interested
parties” decide?
3. EXPERTISE
4. EXPERIENCE
before?
1. EGO
view?
ISSUE
Decisions and 7 questions: a more detailed look

?
DECISION /
JUDGEMENT
ISSUE
What’s my
(“immediate”)
view?
Ego
Taking up an early
stance or opinion ( “early
/ immediate thoughts” )
is often our first step. It’s
expedient and can lead
to rapid decisions but the
problem is that
foundations may be
“undeclared”. It may be
an “intuitive” decision but
alternatively could be a
far more considered
position.
The problem is that
others won’t know and
without further
elucidation, fair debate is
impossible unless all are
in agreement (or we just
vote). So, while it may be
a fair place to start, it’s
not an ideal way to finish
as reaching consensus
will be problematic.

Some possible foundations to our “early
positions”:-
• Conscience,
• Conviction,
• Intuition,
• Feelings,
• Moral sense,
• Moral law or theory,
• Moral maxims,
• Answers to our other questions or
the “Es”
Ego
Back to Index

A modern synthesis
Blackburn’s “Staircase of practical and
emotional ascent”
Judgements
Preferences
Likes / dislikes
Tastes
Hostility
Disgust
Passions
Immediate / “Ego”?
Considered?
Ego

System 1:
skating
System 2:
Writing Sunday’s
sermon?
Rev Robert Walker
1755-1808
Sir Henry Raeburn
Thinking, Fast and Slow; two
systems
Ego and “Thinking fast”

Malcolm Gladwell’s “thin slicing”
“sifting through the situation in front of us,
throwing out all that is irrelevant .. our
unconscious is really good at this, to the point
where thin-slicing often delivers a better
answer than more deliberate and exhaustive
ways of thinking”.
Ego and “Thin slicing”

Pattern recognition
The “Recognition-primed decision (RPD)”
is a model described by Klein which explains
how people can make relatively fast decisions
without having to compare options.
With experience I think we develop the ability
to write or draw “scripts or pictures” of fair
research. As we review more and more
studies, recognition of these “patterns”
speeds and facilitates our judgement. “It just
looks right!”
Analogy can be found in “illness scripts” in
medical diagnostics
(Schmidt HG and Rikers MJP Medical
Education 2007 41 1133).
Ego and “Pattern Recognition”

It makes life difficult for the chair and REC
manager! “Ego” alone provides no “purchase”
for others and, if there is disagreement, all the
REC chair can do is call a vote.
There is a danger of sinking to the level of a
pantomime argument or bar room brawl
Unconscious judgment is recognised to be
subject to error
A dependence on unexamined “Ego” may
promote an egotistical / bullying approach.
Reasons are important. Fair review requires
reasons for any decisions taken. Unexamined
review can hide “self interest, “motivated
reasoning” or “gaming” and hinders
accountability.
Ego and its problems
Judgment under
Uncertainty: Heuristics
and Biases Amos
Tversky; Daniel
Kahneman Science,
New Series, Vol. 185,
No. 4157. (Sep. 27,
1974), pp. 1124-1131.

DECISION /
JUDGEMENT
ISSUE
?
Ego
When might I use this
approach?
• Expected agreement
• No or little moral
quandary
(low moral intensity)
• Low risk
• Familiarity with the area
(pattern recognition)
When might this approach
be problematic?
• New methods
• Controversy
• Seemingly high risk
• Unfamiliarity
Be prepared to be challenged (and
respond fairly). Other foundations…..
What’s my
(“immediate”)
view?

• We need insight to recognise
when we base any opinion or
decision on this approach.
• We need the ability to work
out the foundations of any
“Ego” based view and their
strengths and weaknesses.
• We need to know when this
isn’t appropriate and a
willingness to enter debate.
What does this mean for the REC
member?
Ego
Back to Index

Scenario – Ego
An interview based study, recruiting young adult women, to determine if life stress
precipitates migraine headaches
In the Thames GP research network practices all women aged 20 to 40 with classical
migraine will be asked by their GP if they would consider joining this study. This would entail
a single attendance at the clinic to complete the RD Stress in life questionnaire (fully
validated) and then a 1 hour consultation with the migraine clinic clinical psychologist to help
them manage their condition. They will be given an information sheet and asked if they would
be willing to be rung up by the psychologist in 2 days time. A control group of women
attending for other reasons will also be asked to take part.
Assume everything else is OK.
What are your immediate views on this part of the study AND MORE IMPORTANTLY
WHAT ARE YOUR REASONS?
Put your opinion on this scale - 0 (unwilling to approve) and 10 (willing to approve).
0 5 (undecided) 10
Back to Index

Empathy
Basing decisions on an answer to the
question “How might the participant
decide?” (Empathy) would seem to offer
fair foundations for judgement. It is a way
we can incorporate the views and feelings
of those more closely involved in the
research, into our deliberations.
But empathy is contended. For RECs,
how far can we empathise with potential
research participants about whom we know
so little? We need to accommodate this
criticism and recognise our empathy may
need validation by other approaches.
When they design their work researchers
can help and facilitate their review by
consulting patients and potential
participants to seek their views early on.

We could describe this as going
beyond “putting ourselves in the
potential participants’ shoes”
rather “getting into their brains” to
empathise with their position.
Decisions based on an answer to the
question “How might the participant
decide?” (Empathy) would seem to offer
fair foundations for judgement.
Guidance seems to recognise “empathy”
“2.65 Among the members some
individuals ….should be able to look at the
application from the participants’ point of
view…”
Royal College of Physicians
“RECs evaluate the ethical acceptability of
a research proposal from two main
standpoints, the ethical implications of the
research conduct and from the standpoint
of the prospective research participants
Council of Europe Bioethics steering
committee
Empathy

How researchers can help review
“Researching Research”
Empathy: the researcher’s role

But empathy is contended. For RECs,
how far can we empathise with potential
research participants about whom we know
so little? We need to accommodate this
criticism and recognise our empathy may
need validation by other approaches.
Empathy: its limitations
“as well sympathy between doctor and
patient is surely desirable, and a case might
be made out for the view that only he who
suffers can be the guide and healer of the
suffering. And yet can true spiritual mastery
over a power be won by him who is counted
among her slaves"
Thomas Mann
The Magic Mountain”, p132
In our world, two researchers licking their
wounds after REC review of their project
recognise the use of such empathy (but
question its validity).
“Both researcher and reviewers may have
made the error of assuming that the potential
participants would share their own views.”
Fistein and Quilligan 2012

• We need the insight and
humility to set aside our own
views.
• We need the imagination to see
the project “through the
participant’s eyes”.
• We need the honesty to
recognise limitations to this
empathy.
• We need analytical skills to
confirm or refute any empathy-
based decisions using the other
questions or “Es”.
Empathy
Back to Index

Study
(If you had diabetes) - a study of a biomarker to monitor diabetes, complications,
requiring one blood sample
If you had incurable cancer - a study of a new unproven monoclonal antibody
A questionnaire based study of sex and sexuality
Scenario (1 / 2) - empathy
How willing would you be to join the project described?…
No way! 5 (undecided) Definitely

Group Study
Adult patients with diabetes A study of a new biomarker to monitor
complications, requiring one blood sample
Adult patients with cancer unresponsive to
standard treatment
A study of a new unproven monoclonal
antibody
Undergraduate university students A questionnaire based study of sex and
sexuality
Scenario (2 / 2) - empathy
How willing do you think the following groups would be?…
0 5 (undecided) 10
0 5 (undecided) 10
0 5 (undecided) 10

“I do not believe you can make
moral judgements unless, as far as
possible, you know what you are
talking about…therefore in real
situations you have to take care to
find out as much as you can about
the facts, from experts.”
Warnock M 1998
An intelligent person’s guide to
ethics
Expertise
Here we turn to expertise both in and
beyond the committee to help us.

Application may not be straightforward.
• Guidance documents have varying
authority and are occasionally
inconsistent.
• Guidance may not accommodate all the
details or problems of a specific research
project.
Expertise and guidance: limitations

• We should use expertise to help
us reach our decisions.
• We need to know where to find
expert guidance and analytical
skills to understand it.
• We need to be able to balance
different guidance documents.
• We need to be able to rank
guidance documents in terms of
authority.
• We need to learn how to apply it
to the study before us.
• If decisions run contrary to
guidance we must be able to
present clear reasons.
Suggested resources
Expertise

Scenario – Expertise
Your REC is considering a Phase III randomised controlled trial recruiting children with newly
diagnosed asthma requiring inhaled steroid treatment. They will be allocated (randomly) to
best standard therapy or a new inhaled therapy.
What guidance do you know of?
Click in the box when you want to go back to the figure

It seems reasonable for applicants to expect
to be treated equally. There should therefore
be consistency of process and deliberation.
Review may turn to:
• Past debates (and conclusions)
• Positions previously adopted (“moral or
ethical maxims”)
• Evidence on which past decisions were
based.
Following these will obviously provide
consistency and, given the huge numbers of
decisions expected of RECs and their
members, this might provide an expedient
approach
Experience
“In practice the casuist may
occasionally have been lax; but they
grasped the essential, Aristotelian point
about applied ethics: it cannot get
along on a diet of general principles
alone. It requires a detailed taxonomy
of particular detailed types of cases
and situations.”
Tyranny of principles
Stephen Toulmin
Hastings Center Report 11(6) 31-39
“In almost every case they came close
to agreement even about quite detailed
recommendations – at least as long as
their discussion proceeded
taxonomically taking one difficult class
of cases at a time and comparing it in
detail with other clearer and easier
classes of cases”

Standard 7: Ethical basis for decision-
making in RECs
“When an REC determines that an approach
it has taken on a particular ethical issue in the
past is no longer appropriate, it provides an
explicit rationale for its change in position.”
Standards and Operational Guidance for
Ethics Review of Health-Related Research
with Human Participants, WHO
http://whqlibdoc.who.int/publications/2011/97
89241502948_eng.pdf
But will we be consistently WRONG rather
than RIGHT?
Experience
Half full? / Half empty?

Experience
Applicants to RECs might fairly expect to
be treated equally . There should be
consistency of process and
consistency of consideration.
Reference to past decisions can facilitate
this. Fistein and Quilligan describe how,
despite citing numerous studies that
successfully used recordings of equally
sensitive interactions to improve practice
little attention was paid to this.
Consistency and perhaps justice would
have been better served better by taking
this into consideration.
Fistein E Quilligan S In the lion’s den?
Experience of interaction with research
ethics committees JME 2012 38 224

• We need access to past
decisions (our own or
committee memory).
• We need analytical skills to
compare the past and
current studies and
determine whether previous
decisions are relevant.
• We should be able to
explain why, if relevant, we
haven’t followed such
decisions.
Experience
What does this mean for the REC member?

Where might you find records of past decisions?
a) REC manager
b) Minutes of REC meetings
c) Integrated Research Application System
d) National Research Ethics Advisors Panel
e) Letters to researchers
A researcher presents a study recruiting young adults with inflammatory bowel disease in
which consent will be sought while they attend clinic. He presents a similar previous study
which your committee approved with the same recruitment and consent method
What are the key issues to consider when comparing the current and previous
studies? How might you justify different decision?
Scenario – Experience

• We need skills to find this evidence.
• We need skills to evaluate its
strength and relevance.
• We need skills to apply it to the
study before us.
Evidence (2 of 3)

How might you use evidence in your review?
What are the steps in evaluating evidence in REC deliberations?
Question – Evidence (3 of 3)

There are those who feel it has a role.
Gibson et al report their experience
designing, seeking approval for and
conducting a study into suicidal
ideation. They criticize RECs for an
unempirical approach to risk
assessment and conclude
Evidence: its place
“The above analysis suggests that,
insofar as the REC is tasked with
carrying out a risk assessment, this
must be adequately informed by the
evidence”
Gibson S et al Talking about suicide:
confidentiality and anonymity in
qualitative research. 2012
Nursing Ethics 20(1) 18-29

Evidence can help review:
• Evaluating the consequences of research regulation
• Public perception of research: do people value medical research?
• Determining what matters to patients when we draw up trial endpoints
• Consequences: do participants benefit from research or does research harm?
• Informing potential participant: how do we best do this?
• Determining the consequences of moral positions
• Finding out why people do and don’t take part in research
• Assessing the consequences of trial registration
Evidence: its place
Evidence can establish public opinion:
• What methods of recruitment are acceptable
• Involvement in more than one trial
• Use of personal data
• Use of samples (and acceptable attached conditions)
• Research without consent
• Informing participants of results
• End of trial arrangements
• Accidental discovery of pathology
• Expenses /payments
• Placebo

The WHO Standards and Operational
Guidance for Ethics Review of Health-
Related Research with Human
Participants makes no mention of
evidence but the well respected Royal
College of Physician's guidance makes
frequent reference.
Evidence and guidance
“3.42 evidence suggests that true
refusal rates to inclusion in
observational epidemiological
studies is very low”
“3.42 data suggest …most are
willing to donate samples”
Royal College of Physicians 2007

The place of evidence is contended, frequently
summarised as “is” doesn’t imply “ought”.
As an example Noble sees only a limited place
“If ethical constructs are contingent on outcome
then it might be argued that ethics can and should
be ‘evidence-based’. However, there are good
reasons to argue that at best such evidence can
only inform ethical discourse rather than provide
ethical solutions”
And Salloch et al disparagingly describe it as
“Ethics by opinion poll”
Salloch et al J Med Ethics 2014 40597
Evidence: contrary views

Its quality
Sofaer and Strech conducted a systematic
review of the literature on post-trial access to trial
therapies and identified weaknesses.
N. Sofaer, D. Stretch 2011. “Reasons Why Post-Trial
Access to Trial Drugs Should, or Need not be Ensured
to Research Participants: A Systematic
Review,” Public Health Ethics, 4(2): p.160-184
Its inaccessibility
Dubois argued that a significant amount of
empirical data pertinent to research ethics is
currently inaccessible to RECs or Institutional
Review Board (IRB)
Dubois JM, Volpe RL, Rangel EK. Hidden Empirical
Research Ethics: A Review of Three Health Journals
from 2005 through 2006. J Empir Res Hum Res Ethics.
2008 Sep;3(3):7-18.
Evidence: problems
Index

Conceptual clarity and empirical evidence
are both necessary to address the array of
contemporary ethics issues posed by
informed consent in the context of mental
illness. BUT Scientific inquiry cannot
replace ethical analysis,
Roberts
Philosophical medical ethics is the parent
of empirical medical ethics
Hope1999
Norms and facts should not be seen
as rivals for a sovereign position in
ethical reasoning…norms and facts
should be seen as interdependent …
value judgements play a role (in
appraising evidence)
Strech 2010
Evidence: compromise
But accommodation does seem possible

Evidence: synthesizing views
Today’s evidence based medicine (EBM)
provides a model for accommodation of
judgement and fact in research ethics. One
of its proponents, David Sackett, wrote:
“Good doctors use both individual clinical
expertise and the best available external
evidence, and neither alone is enough.
Without clinical expertise, practice risks
becoming tyrannised by evidence, for even
excellent external evidence may be
inapplicable to or inappropriate for an
individual patient. Without current best
evidence, practice risks becoming rapidly out
of date, to the detriment of patients”
Sackett D 1996 Evidence based medicine: what it
is and what it isn’t.
British Medical Journal 312 71
This could be easily adapted to research
review.
Index

Evidence and empirical facts derived
from research can underpin research
review in many ways.
There is a continuing need to
“research research ethics”.
However, while evidence can be used
to support decisions, facts don’t lead
directly to judgement.
We must also recognise that our
evidence base is currently limited.
Evidence
Index

There are several ethical schools of thought or
models. I mention just three:-
1.The consequentialist (or goal-based) approach
2.The principle based approach
3. A virtue based approach
http://en.wikipedia.org/wiki/Consequentialism
Ethical theories

1. The consequentialist approach
Balancing the benefits of the results of research
against any risks; if benefit outweighs harm this
theory deems an action ethical.
2.The duty based approach
This assesses ethical worth of by processes
involved, doing what is right (and not doing what
is wrong), no matter how important the goals of
may be. The most widely known set of ethical
principles are those described by Beauchamp
and Childress.
Beneficence: a moral duty to do good, to benefit
others
Non-Maleficence: a moral duty to avoid harming
others
Respect for Autonomy: we should allow others to
make decision for themselves
Justice: we should treat others equally
http://en.wikipedia.org/wiki/Consequentialism
Ethical theories
http://www.bmj.com/content/309/6948/184

Ethical Review of Research: An Introduction

Ethical Review of Research: An Introduction

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