Ed 1 Apr 2013

www.crgcp.com 1301: 003

Welcome from our Editor
Articles:
Hello and welcome to this edition of the
Journal of Clinical Research and GCP. 003: Clinical Research in Emerging
With the reaction to a recent Markets: Opportunities and Challenges
pharmaceutical patent case in India I’ve
been thinking a lot about the move towards 007: 5 Golden Rules
conducting clinical trials in developing and
010: Career Corner: Clinical Research
emerging markets. Serge Dehon in his Trainer
article talks about running trials in
emerging markets and we hope to cover 012: Medical Device Regulation & How
more on this subject and also the Things Are About to Change
developing markets in future issues.
There’s so much that we now take for 017: Quick Guide: Increasing Subject
Recruitment
granted here in the west, informed consent,
ethics committee review of research, 018: Organising Successful Events
regulatory authority approval and
inspection. All of these things and more 021: Outsourcing Clinical Trials via
need to be established in places where “Managed Networks”
clinical research is new, and so we must
have a role to play if we want to move
024: Preparing for the Inspectors
clinical trials into these areas.
026: Regulatory Roundup
There are lots of other fascinating articles
in this issue, providing expert advice and 032: CPD/CEU Quiz
practical tips as well as updates on
regulatory changes. Advertisers:

We welcome your feedback, which helps 002: EMEACR
us to continue improving your journal, so
please take a few minutes to visit our 006: PharmaSchool
feedback page. Also don’t forget to
complete our CPD quiz and sign up to get 009: Zig Zag
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011: Delegant Limited

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Contents:


Clinical Research in Emerging Markets
Opportunities and Challenges
By Serge Dehon
CEO of Europe, Middle East and Africa Clinical Research (EMEACR) FZ-LLC

Meeting patient recruitment and enrolment targets is the number one problem in
clinical research globally and this is slowing down drug development. To speed
up drug development, pharmaceutical companies should consider what the
Emerging countries in Middle East, Africa and Asia can offer - access to large
patient pools, as well as local and international expertise.

Getting a head start in the Middle East fastest growing regions in the world,
and North Africa (MENA) markets, with and expected to grow in double digits in
a population of over 350 million and the next few years. It stretches from
counting, could prove to be a strategic Iran to North Africa including big
advantage. For example, some populations like Pakistan (200Million)
countries like Turkey, Egypt, Pakistan, which is the 6th largest country
Iran have huge population who are population of the world, offering a wide
drug naive. range of patients and specific disease
areas.
We believe that the region will grow
further and become the next destination Certain diseases, such as
for clinical research for pharmaceutical, cardiovascular diseases, obesity,
biotechnology and medical device diabetes and its associated disorders,
companies that want to accelerate drug are more prevalent in the MENA region.
and device development. This will be Conducting research in the area would
possible with the right awareness and give a company access to its market
education and the governments in most and patient group, and expertise in the
of the countries are supporting the therapeutic field. Going to the Middle
Clinical Research environment. East is not simply about cost efficiency,
but more about being the first to gain
MENA has a predominantly young access to the target patient population
population compared to an ageing and to accelerate your drug
population in the West. It is one of the development and recruitment process.


in how each country should be
It is also important to note that the
approached and so local knowledge is
experience and expertise in the MENA
key.
region is quite sophisticated and up to
the Western standard because of the
Regional CRO’s such as Europe,
expatriate migration. Many of the
Middle East & Africa Clinical Research
physicians here have trained in major
(EMEACR) have gained this expertise
centers in Europe and the US, which
and we are working with local staff to
translates to international as well as
make sure the Western standards meet
local expertise. This cannot so easily
the local requirements and vice-versa.
be found in other parts of the world.

The CRO industry and clinical research
There is a general lack of awareness of
in general is very young in this region
what the region can offer. People see
and this allows us to grow the industry
the region as one when in fact it is
and learn from other emerging markets
diverse, with many countries at different
that started before us. We have an
stages of development. News on the
advantage, because this region is
political situation here concerns many,
young and evolving, there is a lot of
but it often does not reflect reality.
room for us to grow and to set the
MENA could be compared to Europe.
standards for the region. We are very
There are many different countries but
optimistic that clinical research in the
the world tends to look at it as one big
region will grow to the same level and
piece. There are differences between
quality of Western countries.
the countries and therefore differences

Serge Dehon is the CEO of Europe, Middle East and Africa Clinical Research
(EMEACR) FZ-LLC. EMEACR s a Full Service CRO with HQ in Dubai,UAE and
experience is all phases of clinical research incl. BEBA studies. In addition we provide
through our EMEACR Academy training in Clinical Research including e-learning.
w: www.emeacr.org e: mailto:info@emeacr.org


5 Golden Rules
By Jo Burmester
Director, Global Operations, PharmaSchool Ltd

Working in clinical research can be exciting, interesting and rewarding.
However it can also be difficult and frustrating at times and we all need some
advice sometimes. With this in mind I asked some very experienced clinical
researchers to share their top tip for anyone working in clinical research, and
particularly for those of you just starting out in the field. There were some
themes coming through and I have summarized below in the 5 Golden Rules for
clinical researchers.

1. Make subject protection your top
priority. This is a fundamental
principle of all incarnations of GCP and
regions we are working in. Rationale
for decisions and actions should be
documented in the context of these
should be our guiding light when any requirements and refer to the relevant
decisions have to be made. ICH GCP, legislation and/or guidance. The
for example, states that “The rights, rationale should also take into account
safety, and well-being of the trial rule number 1!
subjects are the most important
considerations and should prevail over Document everything. There’s a
interests of science and society.” The
second principle of GCP is data quality,
3. common
research
saying
– “If
in
it’s
clinical
not
and so this should be the second documented it didn’t happen”. In
consideration in making decisions when other words, for every action and
managing a clinical trial. situation you need a piece of paper
which you can show to an inspector or
Follow the rules. When auditor which shows who did what, and

2. decisions have to be made or
action taken this should always
when. It is important however that any
documentation is appropriate, written
be in the context of applicable by the right person and correctly
regulatory requirements. This can be authorized if necessary.
local, regional or global legislation and Documentation should be factual,
guidance, and it’s important to know objective, accurate and complete.
what the requirements are in the


5.
Manage your time. Working in Expect the unexpected. Another

4. clinical research can
constant juggling act and there
be a commonly cited saying in clinical
trials is “what can go wrong will
are always a lot of things to go wrong”. Planning is critically
remember. We need to be able to think important in running clinical trials and
on our feet, prioritise effectively and there has also recently been guidance
manage a large and diverse workload. issued by some regulatory authorities
There are a bewildering array of time regarding risk assessment and risk
management tools and techniques out based management and monitoring of
there, so our advice would be to try a clinical trials. It’s a fact of life though
few and pick the one which works for that all the planning and risk
you, or perhaps as Adam has done assessment in the world cannot forsee
(see inset) use a combination of a few every eventuality. When the
different ones. unexpected happens we need to be
ready to reprioritise, focus on subject
protection and data quality, and ask for
help if necessary.

I think my one piece of advice would be I think my tip would be to learn some
to 'write it all down'. Be aware of the time management techniques, and
well-known & well-used phrase 'If it isn't come up with a system that works for
written down, it didn't happen'. you. (My own technique is a mishmash
Also, at my age, if it isn't written down, of "do it tomorrow", "getting things
it gets forgotten!! done", and "pomodoro", but it took me
Jane Wallis years to figure it out)
Adam Jacobs
I would say the one piece of wisdom
would be 'Always expect the My advice to anyone new starting out is
unexpected'. The Clinical Trials to assume that what can go wrong will
processes never run as smoothly as go wrong, and to therefore plan
you would hope (and that's even with accordingly. Overcoming the problems
forward planning). Mind you working on to keep a trial on track is what has
a bad trial, can make you realise how proved to me to be the most satisfying
not to do things. Every cloud....... as aspect of what I do. Few trials run
they say. perfectly smoothly. It’s how you handle
Deepika Mistry and cope with the problems that count.
Graeme JT Scott


I think my single biggest tip is to be your study - in the country / continent or
careful to refer proposed actions back therapeutic area that you are working
to regulations / guidelines / SOPs. Then in.
whatever you decide - document the
rationale for it! There is no single way There are many roads to Rome!
to carry out a study and as long as Lizzie Thomson
none of the 'rules' are broken, I would
promote taking an action that works for

Jo Burmester is Director, Global Operations at PharmaSchool Ltd. PharmaSchool is a
leading provider of the full range of clinical research training courses to individuals and
organisations as well as providing a vast range of free online GCP knowledge tests.
w: www.pharmaschool.co e: jo.burmester@pharmaschool.co


Career Corner: Clinical Research Trainer

I always say that training is a bit like writing a novel, everyone thinks they can
do it, but there are particular skills and abilities needed to do it effectively. My
journey to life as a Clinical Research Trainer started out when I took my first job
in a phase I Clinical Trials Unit.

I had wanted to work in clinical rather than just the technical knowledge
research since we first studied clinical I needed to get across. I do feel this
trials as part of my pharmacology has made me a much better trainer and
degree, and the only related job I could I gained so many ideas and techniques
find to begin with was taking blood which have helped in training strategy
samples in the Phase I Unit. It turned development and implementation.
out I was a pretty good phlebotomist In summary if you would like to
and I was soon asked to train all new consider training as a career option I
nursing staff in taking blood samples. would ask yourself the following
This became the highlight of my job, questions:
and I really enjoyed helping people
Do you love sharing information and
learn a new skill and become
seeing others learn?
competent.
Do you know enough about the
I moved on to become a CRA and then information you will need to share?
a Senior CRA, always looking for Are you confident presenting and
opportunities to be involved in training facilitating workshops?
activities, and 5 years later I applied for Are you ready to leave the front line
a job as a full time trainer and was of the operational environment?
accepted. I really enjoyed sharing my
If the answer to all these is yes, then
knowledge of clinical research and
training could be for you. I advise you
GCP with my colleagues, but I felt I
to make sure you have enough on-the-
needed to know more about the
job experience to give you credibility in
process of training so, with my
the eyes of your audience and also to
employer’s support, I enrolled on a
look for a course in teaching or training
distance learning qualification in
which you can do either full-time in
training and development. I learned so
preparation for the role, or alongside
much and it was great to focus on the
your existing job responsibilities.
training process and the learning cycle


Medical Device Regulation & How Things
Are About to Change
By Dr Chris Rowe
Medical Innovation Consultant with Indicium Innovations

There have been a number of incidents, such as the public healthcare scandal
over PIP breast implants, that have combined with increasing expectations and
technological advances to highlight the need to improve the way medical
devices are regulated. This article briefly reviews the way medical devices are
currently regulated and how this is going to change over the next few years.

In the UK both medical devices and process which can take several years
medicines are regulated by the to complete.
Medicines and Healthcare products
Medical devices however are not
Regulatory Agency (MHRA). This
subject to pre-market authorisation by a
organisation was formed by the merger
regulatory body, but to a conformity
of the Medical Devices Agency and the
assessment process. This process is
Medicines Control Agency in 2003.
governed by the Medical Device
Given this fact, it might be surprising to
Directive (MDD), a European Directive
some that the regulatory approach to
which details the pathway needed for a
medical devices has some significant
manufacturer to place a CE marking on
differences when compared to
their device, which is a requirement for
medicines, particularly in the paths
every medical device sold in Europe.
taken to get them to market.
For low risk devices the manufacturer
All medicines must undergo pre-market can actually ‘self-certify’ or more
trials to obtain a Marketing accurately make a self-declaration that
Authorisation or License approval by they have met the requirements of the
the MHRA, with the manufacturers and MDD before putting the CE marking on
distributers licenced directly by the their device and then putting the device
MHRA. Medicines need to be trialled on on the market, although they must
thousands of people before they are register with the MHRA. For medium
licenced using a clear phased trial and high risk devices the manufacturer
needs approval from private sector


organisations called Notified Bodies years, including a requirement for all
confirming that they have met the devices to have clinical evidence to
requirements of the MDD before demonstrate safety. All implantable and
placing the CE marking on their device. class III devices must now undergo
The MHRA is however responsible for clinical trials, or ‘clinical investigations’
auditing the Notified Bodies to ensure which tends to be the term used in the
the quality of their work. medical device world, unless adequate
data can be derived from current
It should be noted that a CE marking is
studies.
not the same as a quality mark or
certification. It just means that the Once medical devices and medicines
company is making the declaration that are on the market there is a lot more
the device meets the minimum similarity in the regulations covering
standards required by the directive. areas such as reporting adverse
incidents and post-market surveillance.
Medical devices are tested for electrical
and mechanical safety but are not This approach had been regarded as
automatically subject to a clinical trial, working well over the last 20 years or
unlike medicines. This is in part due to so, with medical devices being
the vast range of medical devices, available to European patients some 3-
more than 500,000 on the market 5 years earlier than in the USA, with no
ranging from simple bandages and compromise in terms of risk. The
scalpels, to MRI scanners and Robotic European system is also the basis for
Surgery. It is often impractical or many other regulatory systems around
unnecessary to perform clinical trials, the world, including Japan, Australia
devices may be very similar to well and Canada.
proven devices already on the market,
Given the need to improve medical
and issues such as safety and reliability
device regulation the EU Commission
are better tested in laboratory settings.
adopted a ‘package on innovation in
Manufacturers should however be able
health’ on September 26th 2012 for
to support any performance claims they
revision of EU Medical Devices, after a
make for their product, and if this
consultation process that had taken
comes via a clinical trial then
over four years to complete. This
agreement must first be obtained from
proposal will replace the Active
the MHRA.
Implantable Medical Devices Directive
There have been a number of (AIMDD) and the Medical Devices
amendments to the MDD in recent


Directive (MDD), giving the new to some 194 pages, which this article
Medical Device Regulations (MDR). cannot review in detail, but we will
highlight some of the more important
This is a significant change in approach
changes.
as it will now mean regulations rather
than directives are used. This is Scope
important because the exact same There would be a wider scope of
regulations will then be directly in force devices that would come under the
across all countries in the EU, whereas regulations, including implants for
directives are transposed in to national aesthetic purposes or other invasive or
law by each member state, which has implantable devices without medical
led to variations in the law and purpose that are similar to medical
therefore standards. devices. Also non-viable human tissue
and cells that have been substantially
There are a number of key principles
manipulated will come under the MDR,
which the proposed regulatory system
if not covered by the Advanced
is meant to ensure, as follows:
Therapy Medicinal Products (ATMP)
regulations. There is also a new
guarantee the highest level of safety
essential requirement section for
for patients
software, both incorporated and stand
ensures timely access to the latest
alone.
technologies
enjoy the trust of its stakeholders Medical Devices are sub-divided in to
contribute to the sustainability of four risk classes, with are I, IIa, IIb and
national healthcare systems III. Class I are low risk, with Class III
maintains an environment that being the highest risk. The MDD
encourages research and document has a clear review decision
innovation in Europe tree which allows manufacturers to
work out the class of their device and
These may all seem likely fairly obvious
therefor the correct pathway needed to
goals for regulatory system, but it does
get their product to market. The new
acknowledge the balancing act
regulations will change in which class
between providing safe medical
some devices will now sit, including:
devices to the public without completely
stifling their development with onerous Certain devices incorporating
regulations with cost and time nanomaterial will now be moved in
implications. The new regulation to class III
proposal has a lot of detail in it, running


Devices for apheresis will be moved There would be a new Member State
to class III authority body, the Medical Device
Devices composed of substances to Coordinating Group (MDCG) to work
be ingested, applied vaginally, with the commission to improve
rectally or inhaled and are absorbed oversight of Notified Bodies. In
or dispersed in the human body will particular they will be a requirement for
be class III them to review and issue
Devices in contact with spinal recommendations for certification of
column will be moved to a class III class III devices via the Notified Bodies

Regulatory Organisations Companies
There are significant differences on the There would be a need for the
designation and monitoring of Notified manufacturer to employ at least one
Bodies by national authorities around qualified person who possesses expert
Europe. There are therefore not knowledge in the field of medical
surprisingly differences in the quality of devices, similar to the requirements in
the conformity assessment process the pharmaceutical industry. This
performed by them. The national expertise would need to be
authorities such as the MHRA will have demonstrated by either specified
much stronger supervision of the qualifications or five years of
Notified Bodies under the new professional experience in regulatory
proposals to ensure they have the affairs or in quality management
necessary competency to carry out pre- systems relating to medical devices.
market assessment of devices.
There must be an information card for
There would more powers and
implantable devices. This is something
obligations for the Notified Bodies to
that most patients would assume
ensure thorough testing and regular
needed to be done already.
checks on manufacturers, including
unannounced factory inspections and Reprocessors of single use devices will
sample testing. There would also be be assigned same rights and
the requirement to rotate the personnel responsibilities as the manufacturer.
of the Notified Body to balance the Other
knowledge and experienced needed to There would be an extended database
carry out the assessment process with on medical devices on the EU market,
the need to ensure objectivity and with better access to all stakeholders
neutrality in relation to the manufacturer including the public, and stricter


requirements for clinical evidence to Identification (UDI) system will be
ensure patient safety. introduced to improve this process.

There would also be better traceability This will be a significant tightening of
of devices through the supply chain the regulations and will probably take
allowing for more effective responses to until 2014 to be put in to law, with a
safety issues. A Unique Device transitional period of several more
years.

Chris Rowe

Chris Rowe is a Medical Innovation Consultant with Indicium Innovations. His role is
working with Individuals and Organisations to Enhance Medical Innovation.
w: www.indicium-innovations.co.uk
e: info@indicium-innovations.co.uk
t: +44 1491 822 608


Quick Guide:
10 Ways to Increase Subject Recruitment
Recruiting subjects can often be one of the most difficult aspects of an entire
clinical trial. We have asked several experienced people to share their thoughts
with us as to how they look to increase recruitment into their trials. Here are ten
of the best suggestions.

1. Protocol: a well designed protocol with appropriate inclusion/exclusion
criteria and assessments will make sites more likely to recruit
2. Monitor: good on-site monitoring is a very effective way to boost subject
recruitment, as site staff feel supported and the visits act as a milestone for
recruitment
3. Information: provide regular updates to site staff on study progress
4. Advertisements: posters, radio, TV and internet ads can all be used to reach
out to potential subjects. Remember though that these must be approved
by the IEC/IRB BEFORE you use them
5. Database search: Site staff can search patient databases to identify
potentially suitable subjects who can then be approached (appropriately of
course!)
6. Patient support groups: these can be approached to give information about
your study to their members – again all information must be IRB/IEC
approved
7. Aides Memoires: cards with inclusion/exclusion criteria and the recruitment
process can be given to those who will have first contact with potential
subjects
8. Contact other physicians: Primary care physicians could be contacted to
refer potentially suitable subjects
9. More Sites: adding more investigational sites is an expensive option, but
may be worthwhile if subject recruitment is lagging
10. Amend protocol: Are the inclusion exclusion criteria too strict, could you
safely relax them? Are the investigations you are asking for really
necessary, could you reduce the number of visits or tests?


Organising Successful Events
By Angie Major
Managing Director, Delegant Ltd

Clinical Research professionals are experts in GCP, Protocols, SOPs, helping
investigators meet recruitment targets and ensuring all work is conducted to the
myriad of guidelines, local regulatory requirements and 'GCP'. However, at
times there are some challenges that these professionals have no experience
of, no training for and which can be somewhat daunting, e.g.organising an
Investigator Meeting. This article gives some hints, tips and experiences of how
to organise a successful event which might be an Investigator Meeting, CRA
Training or an Internal Conference.

Venue finding – it isn’t just about all you need. For larger events the flow
how many can fit in the room…. of delegates and exhibition floor plan
The venue can have a huge impact on requires working with the venue team
your event. Getting this wrong can be a to plan and manage this successfully.
costly mistake. You want your guests to Can your delegates find their way
have a pleasant experience that's why around the venue easily or is the layout
it is important to get this right. There is confusing? Will you need extra signage
nothing worse than miserable staff, or ushers to help delegates find their
unclean toilets, poor food service and way to meeting rooms? Have you
tasteless coffee. Searching for venues, considered being a mystery visitor and
obtaining proposals, conducting site testing out the check in procedure or
visits and negotiating contracts takes the food in advance?
considerable time. Choosing a venue
Registration – efficiency is the key
can depend on many factors such as
In today’s world of technology
the location, date, size and type of
registering/booking your guests should
property. Consider the message the
be done online wherever possible. It is
choice of venue gives not only about
by far the most efficient way of handling
your event but your organisation too. A
guest registration. Several years ago
worldwide hotel brand 5* venue is quite
we were sent delegate details by email
different to a modern high tech
and then transferred everything on to a
university lecture theatre. Maybe a
database. We used mail merge for
practical training room in a city centre is


confirmation letters and invoices all experience, good venue coordinators
then sent by post. Unsurprisingly many are becoming a rarity with high turnover
documents were lost in the post and in the hospitality industry. Get any
the cost of postage for the large changes or prices in writing and check
number of delegates was notable. the final running order carefully. Make
When we were asked to organise the sure you are completely satisfied
conference again the following year we before approval as this will be the basis
took the registration one step further by for your bill.
connecting the registration on the
Good suppliers are worth their weight in
website directly to a database. It meant
gold. Using ground crew at the airport
delegates would receive automatic
for International meetings can take the
confirmation and we could create an
stress away of the ‘meet and greet’ and
invoice at the click of a button. On
local transportation to and from the
comparing the previous year it saved
airport to the venue. They can alert the
four days of admin time. Since then we
team at the venue that the next large
have continued to develop our own in
group are on their way so they can be
house Online Registration & Invoicing
ready to greet them with a smile.
System which provides:
During the event you will be assigned a
Simple registration venue contact for each day. They are
Banquet tickets included sometimes called Guest Relations
Easy invoicing Manager, Duty Manager, Front of
Dietary needs House etc. Make sure you know who
Hotel accommodation requirements they are, how to contact them when
Real-time data needed and first thing in the morning
Break out session planning that you run through the timings for
each day. They are your ‘right-hand
Team Work – together we can make man’ so to speak so if the coffee runs
a great event low or lunch break will be late they will
A coordinator usually has many people liaise with catering staff to get it sorted
to work with as part of the event team. quickly. They should never be far away
Not only should they focus on their when you need help.
client needs, responding to guest Your staff should be briefed on the
enquiries promptly they also need to venue surroundings, guests with
pay attention to the detail when it special needs, VIPs, timings for the
comes to finalising arrangements with programme and who to contact in case
the venue. This is crucial, and in my of difficulties. The staff on the day will


represent your team and your
And finally, don’t forget to say thank
organisation. Have a briefing session at
you, ask for feedback and wish your
the start of each day to run through
guests a safe journey home.
roles and responsibilities so they know
where they need to be and when.

Angie Major has over fifteen years’ experience of organising events in the healthcare
industry. Angie is Managing Director of Delegant Limited (www.delegant.co.uk) which
is the of events division of Blueberry Business Support Limited
(www.blueberrybusiness.co.uk)


Outsourcing Clinical Trials via
“Managed Networks”
By Ed de Wolf
CEO of FCRA Network S.L.

Winning a bid for a new clinical trial is exhilarating for a Contract Research
Organisation (CRO). It’s the culmination of months of hard work by dedicated
professionals engaged in business development. For the clinical team, however,
it is only the beginning.

All parties involved in clinical trials Each of these solutions has
know how important it is to get to work advantages and disadvantages; it all
with the right people. A competent team depends on the study specifics. As a
can move a project to achieve its goals, rule of thumb, the less experience a
while a team which is badly organized, project team has in a participating
ineffective, and not fully adjusted to a country, the more local expertise they
project´s needs, can bring an entire will need going forward. A Managed
study structure into serious problems. Network can provide a local expert with
indication experience within a
One of the key roles within a project
reasonable budget. They can not only
team is the local senior Clinical
provide the CRA resource, but can also
Research Associate (CRA), contracted
support the study team with local
in each country. These CRAs are
insight, contracting and budgeting, as
responsible for feasibility, regulatory
well as back- up solutions, to ensure
and EC submissions, site contracts,
stability for study management. At the
problem solving and site monitoring.
moment of submitting a selection
For companies which don’t have
request for sourcing a local senior CRA
internal capacity there are several
via a Managed Network, the project
solutions for finding this valuable
team should have the following basic
resource: outsource to a local CRO,
information prepared, which will
hire a freelance CRA directly or co-
facilitate the selection:
operate with a Managed Network of
freelance CRAs.


an estimated scope of work, ideally needs and expectations, and rarely do
completed with estimated time these align. A Managed Network can
allocations, including a provision for assist with checking the scope of work
remote project team communication against local parameters before
and telecalls. selecting and involving a local senior
a task distribution list between CRA. Having this timely input at the
Sponsor, CRO and CRA time of preparing a bid for the countries
task descriptions, to set not covered by the CROs permanent
expectations right staff, can bring business development
start and stop dates, and a timeline teams a valuable advantage at the time
of milestones of negotiation, as they will control more
time and expense sheet templates local detail and will be able to adjust
travel and expense policies their budget accordingly. In turn, this
will help project teams start off with a
The more complete the above
more realistic approach when planning
information is, the more likely it is that
for their timelines, including local legal
the project will attract a high quality
and regulatory requirements.
local professional, who will fit the
company’s work ethic. By providing the input above, the
Managed Network can become a
Even if this basic information is
preferred strategic business partner,
complete, quite often the time
beyond just being a supplier of clinical
allocations for tasks in the scope of
professionals. In an ideal situation, the
work will be insufficient. The reason for
Managed Network and its client start
the incorrect estimation generally lies
complementing each other and through
with the differences in achievement
combining knowledge they can
goals between the business
increase the number of projects they
development team and the clinical
are awarded.
project team. Within the project
structure, both teams have varied

Ed de Wolf
Ed de Wolf is CEO of FCRA Network S.L. www.freelanceCRA.com. This managed
network covers 40 countries, while aiding both CRO and CRA with time saving and
supportive services.
e: ed@freelancecra.com


Preparing for the Inspectors
By Peter Knapp
Associate Director of GCP at ZigZag Associates Ltd

Companies involved in pharmaceutical research will be aware that, following
implementation of EU Directive 2001/20/EC, sooner or later they will have a letter
thud on the mat from their regulatory authority notifying them that they have
been selected for an inspection. In spite of this, a percentage of companies will
do little to prepare for their first inspection until notification arrives and then
panic sets in.

In an ideal world, we are supposed to A very useful exercise is to conduct
be in a constant state of ‘inspection mock interviews; remember that the
readiness’, but who lives in this ideal inspectors can request to interview
world? Rather than wait until the letter anyone in the organisation, not just the
arrives and then run round like ones that you would like to place before
headless chickens, there is a lot that them. It is important therefore that
can be done to prepare in advance for everyone who may be called for
the inspection. Taking advice from interview has an understanding of what
those who have first-hand experience will be required of them in terms of how
of how an inspection works will help to answer questions and project the
considerably to allay the fear of the right attitude. They should be trained to
unknown and give guidance on how to listen to the question carefully and give
conduct the inspection in a way that will an answer only to what was asked.
give the inspectors confidence in the Also it is important that interviewees
organisation. confirm if the question is not within their
remit, or if they do not know the
A gap analysis or mock inspection will
answer, to refer the question to
highlight processes and quality
someone who does.
management systems that need to be
It is important also to have efficient
put into place or improved. If this work
systems on inspection day such as
is put in hand before notification of an
dedicated rooms, host and scribes,
inspection, there will be a good chance
and to provide the inspectors quickly
that this can be fitted around the busy
and efficiently with any document that
schedule of day-to-day work.
they request. It is a good idea to


perform a quality control check and 2. Help staff be more at ease by
photocopy each document before it is providing training and mock
handed to the inspectors, so that a list interview experience
of all documents provided is kept. 3. Mock inspection review or pre-
inspection gap analysis can help
There will always be some last minute
identify issues with documentation
planning for the inspection but if the
and processes in advance.
process for preparing for the inspection
4. If there is no in-house inspection
is in place, the arrival of the inspectors
experience, external consultants
can be awaited in a far calmer
with first-hand experience of
atmosphere.
preparing for and undergoing
inspections can be an excellent
Take home messages: resource.
1. Preparation is key to a good
inspection experience

Peter Knapp is Associate Director of GCP at ZigZag Associates Ltd, providing contract
Quality Assurance and training services to those involved in medical research and
drug development. www.zigzag.eu.com


Regulatory Roundup

New regulations and guidances are commonplace in the world of clinical
research and here we provide a summary of the new documents issued by ICH,
EMA and FDA in the last year. We are only listing documents which are now
final, but there is also quite a bit of draft guidance which has been published,
and of course there has been a draft of the proposed new EU Regulation on
Clinical Trials. These draft documents may be subject to change and so are not
included here. If you know of any new regulatory documents we have missed
please let us know by e-mailing editor@crgcp.com

ICH:

Updated guidance is available for MedDRA version 14.1 and you can find it here:
www.ich.org/products/meddra/meddraptc.html

EU:

Guidance on qualification of novel methodologies for drug development.
According to the document “The EMA qualification process is a new, voluntary,
scientific pathway leading to either a CHMP opinion or a Scientific Advice on
innovative methods or drug development tools” and encompasses things like
imaging methods or biomarkers, or any other new methodology which you wish to
use in pre-clinical or clinical trials. You can find the guidance here:
www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/10/WC500004201.pdf

EMA now has a GCP Q&A section on their website which addresses various
issues. You can find it here:
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_deta
il_000016.jsp&mid=WC0b01ac05800296c5&murl=menus/regulations/regulations.js
p


Guidance on the quality documentation required for biological IMPs. This
document supplements the CTA guidance by outlining additional requirements for
the IMPD for biological products. It also provides examples of changes to the
Biological product which would constitute substantial amendments of the IMPD
and/or CTA. It was issued in May 2012 and you can find it here:
www.ec.europa.eu/health/files/eudralex/vol-10/2012-05_quality_for_biological.pdf

Guidance on medicinal products containing genetically modified cells. This
guidance is about development and evaluation of these products, including of
course clinical trials. You can find this here:
www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/
WC500126836.pdf

The Q&A document in chapter 5 of Eudralex Vol 10 has been updated with one
new question. The question asks how long Annual Safety Reports have to be
submitted in a member state. The answer is until subjects are no longer being
treated in that member state, and this is expected to be last subject last visit unless
otherwise specified in the protocol. You can find the document here:
www.ec.europa.eu/health/files/eudralex/vol-10/ctqa_v10.pdf

Updated guidance on the investigation of drug interactions. “The scope of this
guideline is to provide advice and recommendations on how to evaluate the
potential for drug-food and drug-drug interactions for medicinal products (including
herbal medicinal products) and how to translate the results of these evaluations to
appropriate treatment recommendations in the labelling.” You can find it here:
WC500129606.pdf

As part of the implementation of the new pharmacovigilance legislation the EMA
has issued guidance on post marketing safety studies (PASS) which you can find
here:
WC500129137.pdf This guideline covers both clinical trials and non-interventional


PASS, and sets out scientific and ethical guidance as well as talking about
research which is required as a condition of licence approval.

EMA has also finalised and published the guidance on requirements for biosimilars
which you can find here:
WC500128686.pdf

Reflection paper on GCP aspects of clinical trials conducted outside the EU and
used to support a marketing authorisation application in the EU. The document
outlines the requirements for these trials and it seems likely that further guidance
will be issued at some point. You can find the reflection paper here:

Guideline on the use of pharmacogenetic methodologies in drug development in
products where genetics has an influence on pharmacokinetics. The guideline
discusses situations where pharmacogenetics should be used and then the
requirements and recommendations for those situations. You can find the
guideline here:
WC500121954.pdf

Guidance on posting and publication of result-related information on clinical trials.
This is the implementation of the results section in the EUDRACT database, and
the posting and publication is also considered to be the submission of the Clinical
Trial summary report section of the end of trial notification to the regulatory
authority and Ethics Committee. You can find the guidance here:
www.ec.europa.eu/health/files/eudralex/vol-10/2012_302-03/2012_302-03_en.pdf

Technical guidance on data fields in the results section in the EUDRACT database.
You can find the guidance here: www.ec.europa.eu/health/files/eudralex/vol-
10/2013_01_22_tg_en.pdf


Guidance for GCP inspectors entitled “Points to consider on GCP inspection
findings and the benefit-risk balance”. This guideline categorises the types of
inspection findings which may affect the risk benefit balance for a product and
provides guidance for inspectors in writing inspection reports and also for
assessors when reviewing marketing applications. You can find the guideline
here:
www.ema.europa.eu/docs/en_GB/document_library/Other/2013/01/WC500137945
.pdf

Guidance on the content and format of Final Study Reports for non-interventional
PASS. Obviously interventional post marketing research is subject to the CT
Directive, but non-interventional PASS research should also be written up and this
guideline outlines the requirements for these reports. You can find a copy here:

There is a Q&A section on Paediatric Investigation Plans (PIPs) on the EMA
website. This is for applicants and covers lots of potential questions on the
requirements and process for PIP submission. You can find it here:
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_deta
il_000015.jsp&mid=WC0b01ac0580025b8e

Guideline on investigation of drug interactions came into effect on 1 January 2013.
This guideline “outlines a comprehensive, systematic and mechanistic approach to
the evaluation of the interaction potential of a drug during its development and
offers guidance to ensure that the prescriber receives clear information on the
interaction potential as well as practical recommendations on how the interactions
should be managed during clinical use.” It cover effects of food and interactions
and provides guidance on methods for assessing interactions in vitro and in vivo.
It also provides advice on how to present interaction information in the SmPC. You
can find the guideline here:
WC500129606.pdf


Updated procedure for Orphan Medicinal Product Designation. You can find the
updated document here:

EMA have also updated several of the other guidelines on Orphan products, and
you can find more information here:
www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_co
ntent_000034.jsp&mid=WC0b01ac058002d4eb

Reflection paper issued by the Committee on Advanced Therapies which provides
guidance on classification of Advanced Therapy Medicinal Products (ATMPs). It
states that “The ATMP classification is a non-mandatory, free of charge, legally
non-binding procedure that helps developers to clarify the applicable regulatory
framework.” You can find the document here:
WC500136422.pdf

EMA have advisory groups looking at transparency of clinical trial data, with
emphasis on proactive approaches to publishing data. There has been quite a bit
of output in this area and you can find more information here:
www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/12/
news_detail_001669.jsp&mid=WC0b01ac058004d5c1

FDA

Guidance on IRB continuing review following clinical investigation approval.
This guideline states that IRBs shoud review ongong clinical trials at least
annually and should assess which trials require more frequent review. You can
find the guideline here:
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf


Guidance on Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase
Clinical Studies and Recommendations for Labeling. This guidance looks at
the benefits of considering genetic influences on effectiveness and toxicity of
medicines and approaches to assessing these during drug development. You
can find the guideline here:
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM337169.pdf

Guidance on safety reporting in clinical trials, this is following on from revision
of the safety reporting regulation. The guidance covers requirements for annual
reporting of safety and also expedited submission of SUSARs.. You can find
the guideline here:

There is also additional guidance for small organisations to help them
understand and implement the new requirements. You can find this here:


CPD/CEU Points

If you would like to collect a certificate for 2 CPD/CEU Points/Hours for reading
this edition of The Journal of Clinical Research & GCP please visit
www.crgcp.com and complete the short 10 question test. The test questions are
shown below. The answers to these questions are on the website.

1. What does MENA stand for?
A: Media Naïve Audience
B: Medical Environment for Novel Approaches
C: Middle East and North Africa
D: Median Efficacy Norm for Area

2. ICH GCP states that "the rights, safety and wellbeing of trial subjects should
prevail over" what?
A: Cost
B: Data Quality
C: The protocol
D: The interests of science and society

3. Who provides CE marking for medical devices?
A: Regulatory Authorities
B: Notified Bodies
C: The company who owns the device
D: Medical devices cannot be CE marked

4. What new legislation is being proposed in the EU to cover medical devices?
A: Medical Devices Regulation
B: Medical Devices Directive
C: Active Implantable Medical Devices Directive
D: There is no new legislation proposed, it's just guidance


5. Which of the following would NOT be a suitable way to increase subject
recruitment?
A: TV advertisement
B: Add more investigational sites
C: Reduce the amount of information in the informed consent documentations
D: Increase the monitoring frequency

6. Which of the following would NOT be appropriate to delegate to a Freelance
CRA in a Managed Network?
A: Site Selection
B: Legal responsibility for trial conduct in that country
C: Ethics Committee Submission
D: Problem sovling at investigational sites

7. Who can inspectors ask to see during an inspection?
A: Only those on the list you select for the inspection
B: Only those working on the study being inspected
C: Anyone in the organisation
D: They can't ask to see anyone, but you can provide people for them to interview

8. What is "qualification" for a novel methodology?
A: A scientific pathway leading to either a Regulatory Authority opinion or a Scientific
Advice
B: A statement of the qualifications of the laboratory staff performing the methodology
C: A request from a regulatory authority to justify use of the methodology
D: A statement that the novel methodology is not suitable for use in a clinical trial

9. What does PASS stand for?
A: Pharmaceutical Acceptable Safety Standard
B: Pre-Authorisation Safety Summary
C: Post Authorisation Safety Study
D: Permitted Access to Safety Surveillance

10. According to the new FDA guidance how often should IRBs review ongoing
clinical trials?
A: As stated in their SOPs
B: At least once during the trial
C: At least every 2 years
D: At least annually

Ed 1 Apr 2013

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