Download Protecting Human Subjects in Clinical Trials

JOURNAL FOR
May 2009
U
CLINICAL STUDIES
Your Resource for Multisite Studies & Emerging Markets
FDA Bioresearch
Monitoring
Program
Clinical Trials
In Supportive Care
of Cancer Patients
Australasia
A Stepping Stone to Markets
Paediatric Trials
Not Child’s Play for Insurers
www.jforcs.com
Contents
KEYNOTE ADVISOR
Mark A. Goldberg, MD
MANAGING DIRECTOR
4
Martin Wright
PUBLISHER
WATCH PAGES
6
FDA WATCH
Latest Developments in:
FDA Enforcement
Recalls
Advertising
Clinical Trials
By Joe Pickett of EXPERTBRIEFINGS
8
Protecting Human Subjects in Clinical Trials: The FDA
Bioresearch Monitoring Program
The goals of the FDA’s BIMO Program are to support patient
rights and safety and maintain data integrity in clinical trials.
BIMO is facilitated by inspections of investigators, monitoring of
studies, and laboratory validations throughout international
sites. The four main areas of focus for inspections are sponsor,
monitor or contract research organisations (CROs), the clinical
investigators (CIs), institutional review boards (IRBs), and nonclinical laboratories.
By Regina Ballinger of THOMSON REUTERS
10
Australasia Watch
Australian Clinical Trial Notification (CTN) Scheme, as the
preferred regulatory pathway, underpins the attractiveness of
Australia to product developers both large and small. The CTN is
a notification scheme, and over 95% of all trials conducted in
Australia are approved via this route.
By Russell Neal of Clinical Network Services (CNS) Pty Ltd.
12
Drug Development in China
Related Regulations on Monitoring Period of New Drugs: The
SFDA definitively stated the monitoring period of new drugs in
the Drug Registration Regulation issued in July 2007, as well as
introducing some relevant regulations. The SFDA can set up a
monitoring period for the approved new drug.
By Dr. Xunting Zeng of INCROM CHINA
14
Korea: New ‘Global Hub’ for Multinational Clinical Trials
In recent years, Korea has grown up both nominally and virtually
as the hub of multinational clinical trials. This can be seen as the
fruits of the cooperative efforts made by Korea’s government,
academia and industry to become a medical and healthcare
power nation.
By Kyung Won Jang, of the Korea Health Industry Development
Institute
Mark Barker
MANAGING EDITOR
Jake Tong
EDITORIAL COORDINATOR
Janet Douglas
EDITORIAL ASSISTANTS
Nick Love, Kevin Cross, Lanny McEnzie
EDITORIAL ADVISOR KEYNOTE
DESIGN DIRECTOR
Sureka Dharuman
RESEARCH & CIRCULATION MANAGER
Dorothy Brooks
ADVERTISING SALES
Victoria Winward Zareen Monet
ADMINISTRATOR
Barbara Lasco
FRONT COVER
Inhouse – Design
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2009 PHARMA PUBLICATIONS
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JCS 1
Contents
16
18
The Global Crisis: An Advantageous Momentum
for Latin America
“Will Latin America continue to be seen as a region
of opportunity for the global industry?” Will they
(sponsors and CROs in the Northern Hemisphere
alike) capitalise on the huge opportunities which
are present here?
An insight by Oscar Podesta of CHILTERN – Latin
America.
Paediatric Trials – Not Child’s Play for Insurers
Chris Tait of Chubb Insurance Company of Europe
SE, as an underwriter asked to insure sponsors' legal
liability arising from clinical trials on children,
examines the liability issues and asks; with
regulations in place how do insurers go about
assessing risks in paediatric trials?
REGULATORY
20
Takeaways for Emerging Countries’ Clinical Trial
Conduct
Dr Nermeen Varawalla, reviews DIA Euro Meeting,
Berlin 2009
26
Establishing of infrastructure for ethical review
in Kazakhstan
Modern development of science and technology is
typically accompanied with increased public
attention to ethical and legal aspects of scientific
research. There is a systematic implementation of
ethical principles in areas of science in Kazakhstan, as
well as in other Central Asian republics. Prof. Bakhyt
Sarymsakova evaluates the legal infrastructure in
place.
Donna Beardsworth of Beardsworth Consulting
Group discusses the Supportive Care Trial challenges.
34
Interview with ACM Global Central Laboratory
Dr. T.S. Jaishankar CEO of Quest Life Sciences &
Member of the JCS Editorial Advisory Board talks
with Elena Logan & Kathleen Murray of ACM Global
Central Laboratory on the requirements from a
Testing Laboratory in Oncology Studies
36
Interview with Medidata Solutions Worldwide
Dr. Patricia Lobo, Senior Consultant of Life Science
Business Consulting & Member of the JCS Editorial
Advisory Board discusses with Steve Heath & David
Quarm of Medidata Solutions, the application of
data collection and analysis, for the early detection
of Breast Cancer.
Study Paper
40
QTc Prolongation in Patients with Chronic Renal
Impairment
Patients with end-stage renal disease are frequently
associated with increased mortality rates due to
sudden cardiac events. Ventricular arrhythmias are
the major problems of cardiac origin in this
population. Several attempts have been made to
determine factors responsible for the occurrence of
serious ventricular arrhythmias. This investigation
was performed to elucidate a possible correlation
between the status of renal impairment and QTc
prolongation in patients with different stages of
renal impairment and healthy controls.
By Cornea N., Wadepuhl M., Tsvitbaum N.,Janik F.,
Eckl K.M.
IT & LOGISTICS
MARKET EVALUATION
28
Interview with Congenix
Prof.Bakhyt Sarymsakova, Head of Department of
International Cooperation National Research Center
of Mother and Child Health & Member of the JCS
Editorial Advisory Board discusses the present
climate for conducting Clinical Trials in Russia &
Eastern Europe with Irina Dobreva & Vladimir V.
Novakovskiy of Congenix LLC – A CRO’s perspective
44
SUBSECTION
THERAPEUTIC STUDIES
Oncology Series
31
2 JCS
Understanding and Addressing the Unique
Challenges of Clinical Trials in the Supportive
Care of Cancer Patients
Researchers supported by government, academia
and industry work diligently to develop safe and
effective medicines to prevent and treat cancer, and
to ameliorate side-effects of treatment. Although
there are many research objectives, the primary
goals are to increase survival, decrease side-effects,
and maintain or recapture quality-of-life for cancer
patients in all stages of their disease and treatment.
Digital pen and paper help UN body fight
disease in Africa
The United Nations Food and Agriculture
Organization (FAO), is using Digital Pen and Paper
technology to virtually eliminate the need for
‘traditional’ data entry, enabling near-instant field
reports to prevent or limit the effects of infectious
diseases, drought and flooding in sub-Saharan Africa.
Urban Fröderberg of Anoto Group AB explains.
49
Australasia - your stepping stone to market
Australasia is frequently used as a term to describe
the region of the world that encompasses Australia
and New Zealand together with the many Asian
nations immediately to the North. In this special
sub-section, researchers and managers active in
several organisations from Queensland, Australia,
provide an insight into the clinical and translational
research capabilities in Australia and New Zealand,
with an emphasis on the former.
Section Compiled by QCTN (Queensland Clinical
Trials Network Inc.)
www.jforcs.com
Editorial Advisor Keynote
By Mark A. Goldberg, M.D., Chief
Operating Officer, PAREXEL International
The theme for the 45th Annual DIA
Meeting to be held in San Diego, California is
“Better Medicines: Improving Safety with
Every Step.” This seems an apt theme,
particularly against the backdrop of the
Obama administration’s likely focus on safety
and comparative effectiveness in drug
development. Safety will remain paramount
in the global search for effective new
therapies.
With the knowledge that many potential adverse events will not emerge until
much larger populations of patients are exposed, proactive pharmacovigilance
planning is a growing focus for the biopharmaceutical industry. Voluntary
reporting of adverse events is being replaced by registries and newer forms of
non-interventional studies that will better characterise the profiles of marketed
treatments. Technology has a key role to play in this area. An example is the
potential that electronic medical records hold to mine data for safety signals,
with the requisite protection of personal information, without having to use
either specially designed studies or to rely on physician reporting. The approach
to safety concerns is also evolving as companies implement new Risk Evaluation
and Mitigation Strategies (REMS).
In early phase studies, a goal will be to generate more comprehensive safety
profiles of compounds. This will be facilitated by innovative trial designs,
including the use of adaptive studies. In addition, the role of biomarkers will
continue to evolve as a tool to better predict potential safety issues as well as
efficacy.
It is anticipated that medications that more specifically target the underlying
mechanisms of disease will also have more attractive safety profiles. While the
emergence of personalised medicine and the pairing of treatments and
diagnostics may be progressing more slowly than some had expected, this area
remains an inevitable evolution for the biopharmaceutical industry.
This year’s Annual Meeting will bring representatives of the biopharmaceutical
industry together at a time of heightened uncertainty. The industry faces
pressures due to global economic challenges, patent expirations, and decreased
R&D productivity among other factors. In the U.S., the direction of the new
administration, beyond the safety considerations mentioned earlier, is still
emerging and includes such considerations as drug importation, pricing, and
reimbursement. With large mergers and acquisitions changing the landscape,
the industry will likely experience additional shifts in drug development
priorities.
Combined with these market dynamics are a few key trends that continue to
shape the biopharmaceutical industry, including increased globalisation of drug
development, continued adoption of eClinical technologies, and the growing
importance of strategic partnerships between CROs and pharmaceutical
companies.
•
Increased globalisation of drug development is being driven by
several factors, including the ability to access diverse patient populations and
the lower cost of conducting quality clinical research in emerging geographies.
Another major driver is the increasing importance of new end markets for
biopharmaceutical products in a number of geographies, including India and
China.
•
The use of technology has progressed from the adoption of a
disparate set of tools from various vendors to the increasing availability of
integrated technology suites. These suites offer the potential to meaningfully
decrease cost and ease system interoperability. Combining these technology
platforms with clinical expertise will help to bring greater productivity to
development programs.
•
Evolving strategic relationships among service providers and
sponsors will lead to new operating models and the emergence of best practices
in partnering. These enhanced partnerships, which will create new expectations
of CROs in the areas of expertise and relationship management, promise to
bring greater innovation and efficiencies to the drug development process.
Since change creates opportunities, it is likely that many of these emerging and
ongoing trends will be favourable for the biopharmaceutical services industry,
despite the current economic environment. The hope is that industry
challenges will further drive innovation and enhance the performance of R&D
investments. Service providers have an important role to play, in partnership
with sponsors, to fulfil that promise. Given the many significant and evolving
dynamics, this year’s meeting promises to foster an interesting dialogue among
industry participants.
Editorial Advisory Board
Art Gertel, VP, Clinical Services, Regulatory & Medical writing,
Beardsworth Consulting Group Inc.
Hermann Schulz, MD, CEO, INTERLAB central lab services –
worldwide GmbH
Maha Al-Farhan, Vice President, ClinArt International, Chair
of the GCC Chapter of the ACRP
Bakhyt Sarymsakova - Head of Department of International
Cooperation, National Research Center of MCH, Astana,
Kazakhstan
Janet Jones, Senior Director, Strategic Patient Access, KENDLE
Nermeen Varawala, President and CEO, ECCRO - the pan
Emerging Country Contract Research Organisation.
Catherine Lund, Vice Chairman, OnQ Consulting
Jeffrey W. Sherman, Chief Medical Officer and Senior Vice
President, IDM Pharma. Board Member of the Drug Information Association.
Chris Tierney, Business Development Manager, EMEA
Business Development, DHL Exel Supply Chain, DHL Global
Chris Tait, Life Science Account Manager, CHUBB Insurance
Company of Europe
Devrim Dogan–Guner, Medical Director, ENCORIUM
Francis Crawley. Executive Director of the Good Clinical
Practice Alliance – Europe (GCPA) and a World Health
Organization (WHO) Expert in ethics
Jerry Boxall, Managing Director, ACM Pivotal.
Patricia Lobo, MSc. PhD. Managing Director & Senior
Consultant, Life Science Business Consulting.
Peggy A. Farley, President and Chief Executive Officer of
Ascent Capital Management Inc.
Kamal Shahani, Managing Director of Cliniminds - Unit of
Teneth Health Edutech Pvt. Ltd.
Russell Neal, COO, Clinical Network Services (CNS) Pty. Ltd.
Karl M Eckl, Co-founder, Executive and Medical Director,
InnoPhaR Innovative Pharma Research Eastern Europe GmbH
Rob Nichols, Director of Commercial Development, PHASE
Forward
Linda Zao, President and CEO, Draco Healthcare Consulting
LLC.
Stanley Tam, General Manager, Eurofins MEDINET
(Singapore, Shanghai)
Liz Moench, President and CEO of Medici Global
Stefan Astrom, Founder and CEO, Astrom Research
International
Georg Mathis Founder and Managing Director Appletree AG
Mark Boult, Healthcare Market Sector Leader, DNV
Ghassan Ahmed, Vice President, Medical & Regulatory
Affairs, ClinArt International
4 JCS
Steve Heath, Head of EMEA - Medidata Solutions, Inc
Mark Goldberg, Chief Operating Officer, PAREXEL
International Corporation
T S Jaishankar, Managing Director, QUEST Life Sciences
www.jforcs.com
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FDA WATCH
ENFORCEMENT
FDA announced on April 10 that it had obtained a permanent injunction
barring Neilgen Pharmaceuticals Inc. of Westminster, MD., its parent
company, Advent Pharmaceuticals, Inc. (Advent), of East Windsor, N.J., and
two of their officers, Bharat Patel and Pragna Patel, from manufacturing
and distributing any unapproved, adulterated or misbranded drugs.
Both Neilgen, which does business as Unigen Pharmaceuticals Inc.
(Unigen), and Advent are contract manufacturers and distributors of more
than 25 different unapproved drug products each. The more than 50
unapproved drug products primarily include prescription cough and cold
products. The unapproved drugs manufactured by Unigen and/or Advent
include, but are not limited to:
•
•
•
•
•
•
•
•
RE All 12 Suspension;
BP Allergy Junior Suspension;
PE Tann 20 mg/CP Tann 4 mg Suspension;
BP New Allergy DM Suspension;
D-Tann CT Tablets;
B-Vex D Suspension;
Histex SR; and
Chlorpheniramine Maleate 12 mg/Pseudoephedrine HCl 120
mg LA Tablets.
The unapproved drugs manufactured by these companies have not
undergone the FDA's drug approval process, so their safety and
effectiveness have not been established and the FDA has not reviewed the
adequacy and accuracy of the directions for use and warnings on the
labelling, FDA stated in its press release.
For more information, please visit: www.fda.gov
RECALLS
FDA adopts interim plan to avoid shortage of opioid
FDA on April 9 amended its March 30 action warning manufacturers to
stop the production and distribution of certain unapproved prescription
opioids, to allow the continued marketing and distribution of one particular
type of opioid - a high concentrate morphine sulfate oral solution - on an
interim basis.
FDA took this action in response to concerns from patients and
healthcare professionals in the palliative care community that the action
taken on March 30 would cause a shortage of 20 mg/ml morphine sulfate
oral solution, the agency stated in a press release.
This product is widely used to alleviate pain in terminally ill patients.
The agency has determined that this dosage form is medically necessary,
and should remain on the market until an approved alternative becomes
available to the patients that need it.
“While the FDA remains committed to ultimately ensuring that all
prescription drugs on the market are FDA approved, we have to balance
that goal with flexibility and compassion for patients who have few
alternatives for the alleviation of their pain,” said Douglas Throckmorton,
M.D., deputy director, FDA’s Center for Drug Evaluation and Research. "In
light of the concerns raised by these patients and their healthcare
providers, we have adjusted our actions with regard to these particular
products."
For more information, please visit: www.fda.gov
6 JCS
ADVERTISING
FDA rules on drug ads cause confusion in web advertising
FDA sent letters to 14 major pharmaceutical companies late last month
with a strong warning: the companies’ search advertisements — the short
text ads that run beside Google results — had to start including risk
information about each drug or else be rewritten or removed, according
to The New York Times on April 17.
Just how the companies were supposed to comply was not so clear. In
the 95 characters that Google allowed for search ads, there was no way to
include all the required information, the companies argued.
Now, as the companies change their search ads to comply with the
letters, industry executives say the solution is worse than the problem: their
ads are even more confusing and misleading now, they say. And they worry
that regulators will enforce standards that were created for magazines and
television, rather than making new rules that acknowledge how internet
ads have evolved.
The letters were sent to almost all of the major pharmaceutical
companies, including GlaxoSmithKline, Pfizer, Merck and Eli Lilly. The letters
said ads for widely prescribed drugs, including Celebrex, Propecia and Yaz,
did not include the paragraphs of precautions the agency required.
Though the texts of the ads varied, the agency’s objections to each ad
were similar. One such ad was for Merck’s allergy drug Singulair. The ad
read, “Allergy Medication Relief of Allergy Symptoms: Learn About a
Treatment Option. www.SINGULAIR.com.”
For more information, please visit: www.nytimes.com
CLINICAL TRIALS
FDA takes action against firm in human experiments
Citing serious violations uncovered by a congressional probe, federal
regulators on Tuesday imposed restrictions on a company that monitors
testing of experimental drugs and medical devices on human beings, the
Associated Press reported on April 17.
The Food and Drug Administration sent a warning letter to Coast IRB,
saying regulators identified "serious violations" of federal rules that protect
human subjects, and are concerned about risks to patients. The Colorado
Springs, Colo., firm agreed to stop reviewing new experiments and also halt
enrolment in research trials already underway.
Independent expert review of clinical trials is an integral part of the
development of new drugs. But a congressional hearing last month
exposed flaws in the system. Undercover investigators for the Government
Accountability Office were able to get Coast IRB's approval for a fictitious
testing protocol that supposedly involved pouring a litre of a product into
a woman's stomach following surgery. Two other companies approached
by GAO rejected the proposal.
The FDA's action will affect some 300 human studies involving about
3000 researchers. Coast IRB will have to show regulators it is fully
complying with all rules that govern experiments on humans before the
restrictions can be lifted.
Coast IRB did not respond immediately on April 14 to a request for
comment. In the past, company officials complained the firm was
"hoodwinked" by investigators, but said they have since made changes. I
Joseph Pickett is Owner and President of Expertbriefings.com, a
leading provider of regulatory teleconferences in clinical trials,
pharmaceuticals, medical devices and biological products. For more
information, please visit http://www.expertbriefings.com, or
Email: [email protected].
www.jforcs.com
PROTECTING HUMAN
SUBJECTS IN CLINICAL
TRIALS: THE FDA
BIORESEARCH MONITORING
PROGRAM
Agencies under the purview of the United States (US) Department
of Health and Human Services (HHS) have multiple initiatives to
improve human subject protection (HSP). One such agency - the US
Food and Drug Administration (FDA) - manages the activities of the
Bioresearch Monitoring and Inspection Program (BIMO) mandated
by the US Congress in 1976.
The goals of the FDA’s BIMO Program are to support patient rights and
safety and maintain data integrity in clinical trials. BIMO is facilitated by
inspections of investigators, monitoring of studies, and laboratory
validations throughout international sites. The four main areas of focus for
inspections are sponsor, monitor or contract research organisations (CROs),
the clinical investigators (CIs), institutional review boards (IRBs), and
non-clinical laboratories.1
According to BIMO’s 2007 inspection records, the FDA conducted a
total of 1024 inspections, half of which were minor.2 Minor inspection
findings are classified as no action indicated (NAI) signifying that no
objectionable conditions were noted during the inspection. About half of
all violations occur at the investigator site. Of the more serious violations
that did occur, 86% were in study protocol violations and record keeping.2
More serious violations are classified in one of two ways:
1.
2.
A Voluntary Action Indicated (VAI) notes that objectionable
conditions or practices were found during an inspection. VAIs
will typically lead the FDA to generate a warning letter to
indicate that corrective action is necessary.
The most serious violation is an Official Action Indicated (OAI)
which means that objectionable conditions or practices
representing significant departures from the regulations were
observed. An OAI finding on an inspection will generally result
in a warning letter and/or administrative and regulatory
sanctions.
During BIMO inspections, there are several focus points that will provide
clues to the presence of fraudulent data in clinical trial records. The FDA
provides inspectors with guidance on identifying fraud during BIMO
inspections:3
•
•
•
8 JCS
Identify original source data and verify its existence and
accuracy against what are reported to FDA.
Missing records are a key indicator of potential fraud. Demand
to see all the original source data and supporting data as
identified from the protocol.
Fabricated data will point in the direction of inconclusive results
or results favouring test article.
•
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Observe if all documents are prepared or written by the same
person and question whether others should have been involved.
Notice the repeated pattern of data from a study. Identify
departures from anticipated trends.
Be alert to whether the firm has the expertise, capability, and
equipment to perform the procedure or test associated with
the data.
Determine the sequence of events and amount of work related
to generating the data and consider whether it was physically
possible for the individual(s) performing the procedure to have
done so in the timeframe and sequence indicated by the
records.
In 2006, the FDA launched the Human Subject Protection-BIMO Initiative
to modernise the programme. A number of FDA regulatory actions have
resulted including the publication of several more recent guidances to
assist parties in understanding the BIMO program. I
References:
1. US Food and Drug Administration Office of Invitro Diagnostics [Slide
Presentation]. Building Quality into Device Clinical Trials. April, 2006. Available at:
http://www.fda.gov/cdrh/oivd/meetings/041806agenda.html. Accessed February 14,
2009
2. Drug Information Association Annual Meeting 2008 [Presentation]. Compliance
Trends in Clinical Research.
3. US Food and Drug Administration. Inspection Guide: Detecting Fraud in
Bioresearch Monitoring Inspections. April 1993.
4. US Food and Drug Administration. Guidance for Clinical Investigators, Sponsors, and
IRBs: Adverse Event Reporting - Improving Human Subject Protection, 15January-2009.
5. US Food and Drug Administration. Guidance for Industry and Food and Drug
Administration Staff; The Review and Inspection of Premarket Approval
Applications Under the Bioresearch Monitoring Program, 8 January 2008.
6. US Food and Drug Administration. Draft Guidance for Industry: Protecting the Rights,
Safety and Welfare of Study Subjects - Supervisory Responsibilities of
Investigators, May 2007.
Regina Ballinger, RN has been with Thomson Reuters for 6
years specialising in pharmaceutical regulatory affairs. She
currently manages editorial content for the IDRAC
regulatory database. She has been employed in the
healthcare industry for over 15 years and has extensive
experience in health education.
Email: [email protected]
www.jforcs.com
AUSTRALASIA WATCH
Welcome to our second Australasia Watch. This month I aim to shine
a little light on the Australian Clinical Trial Notification (CTN)
Scheme which, as the preferred regulatory pathway, underpins the
attractiveness of Australia to product developers both large and small.
The CTN is a notification scheme, and over 95% of all trials conducted
in Australia are approved via this route, where the onus is on the Human
Research Ethics Committee (HREC) to bear the responsibility for
approving:
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the safety and efficacy of the medicine or device
the ethical acceptability of the trial process
approval of the trial protocol, and
evaluating the scientific merit of the trial.
One of the most common questions asked by sponsors considering using
Australia is “Who completes the CTN submission?” As the Australia
Therapeutic Goods Administration (TGA) does not review any data relating
to the clinical trial under this scheme, one can consider the HREC as the
regulator under the CTN scheme. In other words, when an investigator
submits to their HREC, should they approve, typically within four weeks,
and then if the HREC should raise questions going on to eight weeks, the
investigator is getting both ethics and regulatory approval. The TGA does
receive notification of the HREC approval via receipt a completed and
signed CTN form, which they acknowledge in writing within 10 days of
receipt of the signed CTN form and appropriate payment.
Where the study is a first-in-human study, it is common for the TGA to
request copies of the protocol and IB at some stage after issuing a letter
of acknowledgement and on occasion it may request some additional
information. The TGA is empowered to place an ongoing study on “Clinical
Hold” should their concerns be significant. This is extremely rare and likely
only to affect Phase I studies being conducted under a CTN.
So who completes the submission and what does one need to submit?
An HREC submission is prepared by each investigational site’s Principal
Investigator, with of course appropriate assistance from the sponsor or
CRO. The “standard” submission can vary slightly from site to site, but
typically includes:
•
•
A completed CTN form, signed by the Australian sponsor
Completed HREC application form (increasingly the National
Ethics Application Form, or NEAF, is used)
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Final protocol
•
Current / up to date Investigator’s Brochure (IB)
•
Site-specific patient information sheet/informed consent form
•
Fully signed Medicines Australia Form of Indemnity
•
Copy of the Clinical Trial Insurance (CTI) with sufficient
coverage to satisfy varying levels across Australia (check with
your CRO or site to be sure. Note where a CRO is the Australian
sponsor, many HRECs require that such parties are listed or
named on the CTI
•
If the study is a first-in-human study, the HREC may request
that an Independent toxicologist’s report, or similar, is also
provided.
It is worth emphasising here that we avoid a full regulatory submission
such as an IND equivalent, but the quality of the submission, particularly
the IB, should be of a standard that would be accepted by any
international regulator.
A separate CTN form must be completed for each potential trial site,
and once the submission and payments have been posted to the TGA the
trial may commence, though it is prudent to await the letter of
acknowledgement before treating the first volunteer.
By now you may have discovered the Australasian pull-out section in
this month’s JCS, and hopefully I have added some supplementary detail
to the articles featured and confirmed the simplicity and attractiveness of
the Australian CTN Scheme. I
Russel Neal With almost 20 years working in the healthcare
industry, for the last 16 years Russell has been advising
clients in clinical trial management in a career spanning
Europe Asia and Australasia. He is currently Chief Operating
Officer at Clinical Network Services (CNS) Pty Ltd, a privately
owned, Brisbane based, full service contract research
organisation (CRO) providing clinical management support
and services to the healthcare community particularly
during the early phase clinical development of their
products. Email: [email protected]
DRUG DEVELOPMENT IN
CHINA
Related Regulations on Monitoring
Period of New Drugs
The last issue mainly introduced the Special Approval Regulation on
New Drug Registration, showing that the SFDA (State Food and Drug
Administration of China) is determined to encourage innovation and
strengthen risk control. Meanwhile, in order to protect public health,
the SFDA definitively stated the monitoring period of new drugs in
the Drug Registration Regulation issued in July 2007, as well as
introducing some relevant regulations. The SFDA can set up a
monitoring period for the approved new drug. The monitoring period
is calculated from the approved date of new drug production and it
must be within five years.
Within the monitoring period, the SFDA will not grant approval to any
other manufacturer to produce, change the form of or import the new
drug. From the first day of the monitoring period, the SFDA will not accept
same–type registration applications from other applicants; other
applicants’ same-type applications that have been accepted but not
approved for performing drug clinical tests will be returned. If the
applications are approved for performing drug clinical tests, they can
continue to be handled according to the Submission and Approval
Procedures of Drug Registration. If the application meets the related
requirements, the SFDA will approve the drug production or import, and
then perform the monitoring along with all the other approved same-type
drugs. Only after the monitoring period of new drugs can other applicants
apply for imitation or import.
Time Limit Table on Monitoring Period of New Drugs
(Note: the monitoring period is only used for new drugs under the following conditions)
1.1
1.2
1.3
1.4
Drugs that have fewer components and
are made from marketed
multi-component drugs.
1.5
New compound formulations.
2
3.1
During the monitoring period of the new drug, the manufacturer’s duties
are as follows:
3.2
1.
2
The drug manufacturer should inspect the production process,
quality, stability, efficacy, adverse effects etc. of the drug, and
should report annually to the local drug administration agency.
The drug manufacturer should start to produce the new drug
monitored within two years after the approved production
date. Otherwise, the SFDA can approve other drug manufacturers’
applications for its production, and monitor it again.
Formulations in which the APIs are
made by synthetic or semi-synthetic
methods.
Formulations in which the new effective
monomers are extracted directly or by
fermentation from natural materials.
Formulations that are optical isomers of
known drugs and made by means of
resolution, synthesis etc.
3.3
Formulations in which the
administration routes are changed but
not on the national and international
markets.
Internationally-marketed formulations,
with or without changed drug forms,
and with unchanged administration
routes.
Internationally-marketed compound
formulations, with or without changed
drug forms, and with unchanged
administration routes.
Internationally-marketed formulations
with changed administration routes.
4
Marketed formulations in which the acid
radicals, basic groups or metal elements
are changed, but the APIs with
pharmacological effects are unchanged.
5
Nationally-marketed formulations in
which the drug forms are changed, but
the special techniques on the drug
administration route (such as targeted,
slow-release and controlled-release
techniques) are unchanged.
Dr. Xunting Zeng has decades of experience in the field of Clinical
Trials. Dr. Zeng received his PhD at Kansai Medical University, Osaka,
Japan. Since then he worked as Special Investigator at International
Medical Centre of Japan. Later he joined InCROM Group, a Japan
based leading international Contract Research Organisation firm. Dr.
Zeng is currently General Manager of InCROM China and heading up
to elevate China clinical trial with global standard.
Email: [email protected]
12 JCS
www.jforcs.com
KOREA: NEW ‘GLOBAL HUB’
FOR MULTINATIONAL
CLINICAL TRIALS
Clinical Practice) guidelines. In 2001, Korea expanded its clinical trials by
introducing the IND (Investigational New Drug Application) in order to
reach the required standards of other advanced countries. Also, the
government established KoNECT (Korea National Enterprise for Clinical
Trials) and selected 12 local clinical trial centres with three more to be
selected this year, giving a total of 15 local clinical trial centres to manage.
KoNECT will expend all its resources in supporting the facilities, equipment
and human resources of the pharmaceutical companies. In addition, it
helps the success of the local clinical centres by supporting management
system and other bases for the specialisation and professionalisation of
the centres.
Various aspects can illustrate the competitiveness of Korea as the hub
for clinical trials. Currently, the number of clinical trials in Korea exceeds
400, making it the 26th most active country in the world, 4th in Asia
following Japan, India, and China.
Including 215 multinational clinical trials performed in 2008, the total
number of approved clinical trials in Korea leaped to 400, resulting in a
38.9% increase from the annual average.
Number of Approved Clinical Trials: KFDA, 2008
A successful clinical trial is one of the most significant procedures in
developing new drugs for the eradication of disease and the
promotion of human health. Since clinical trials help confirm the
safety and efficacy of the drugs, high-technology and well-designed
protocols as well as cost-effectiveness and rapidity are all critical
matters which should not be simplified.
In recent years, Korea has grown up both nominally and virtually as the
hub of multinational clinical trials. The number of multinational
pharmaceutical companies promoting their multinational clinical trials in
Seoul has been increasing exponentially. This can be seen as the fruits of
the cooperative efforts made by Korea’s government, academia and
industry to become a medical and healthcare power nation. These three
powers have combined to instigate efforts to make Korea an advanced
nation in regulatory science and operation systems, as well as to raise the
level of skill and manpower for a successful clinical trial. Korea activated
mandatory GCP (KGCP) in 1995 and introduced bridging trials for the
domestic application of foreign clinical trials in 1999. In 2000, Korea’s
standard for clinical trials was revised to conform to the ICH E6 (Good
Korea has made dramatic advances not only in quantity, but also in quality,
showing remarkable increases in Phase I and II trials compared to Phase
III trials which used to be the dominant studies conducted in Korea. The
early stage clinical trials, in which the first drug administration test is
performed on the human body, is the most delicate and critical step in
developing new drugs, thus, the increase in the early phase studies implies
that Korea has enhanced its overall clinical trial reputation. The fact that
multinational pharmaceutical companies have been continuously
increasing the number of clinical trials in Korea testifies that they are
paying attention to Korea, considering it as the potential hub for
multinational clinical trials in Asia.
In addition to its improvement in clinical trial performance, Korea is to
establish the APEC Harmonization Center to contribute to global
harmonisation of regulatory guidelines through educational workshops.
Its initiative is expected to play a key role in the international
harmonisation of the pharmaceutical development standard. The title
“Multi-Regional Clinical Trials Seoul Workshop – Inaugural workshop of the
APEC Harmonization Center” was given to the opening ceremony at the
Seoul workshop, scheduled for June 15th, shows the efforts of Korea to be
a true global clinical trial hub. KHIDI (Korea Health Industry Development
Institute), which functions for the development of healthcare in Korea, has
overseas branches in Beijing, Singapore and New York. In addition to
inquiries regarding clinical trials, all cooperation and collaboration with the
Korean healthcare industry and community will be taken care of through
KHIDI and its branches. I
Kyung Won Jang, PhD. Dr. Jang worked as head researcher at KHIDI
(Korea Health Industry Development Institute), the government
affiliated organisation established to promote Korea’s healthcare
industry. Dr. Jang is currently the director of Center for Global Healthcare
Business at KHIDI and also is associate director of APEC Harmonisation
Center. Emails: [email protected] (US, Canada, Latin America);
[email protected] (Asia and Pacific); [email protected] (China)
14 JCS
www.jforcs.com
THE GLOBAL CRISIS: AN
ADVANTAGEOUS
MOMENTUM FOR LATIN
AMERICA
As the books say, every crisis should be seen
as an opportunity. It is also a fact that in
times of uncertainty, innovation is a very
important tool.
During the last few months, everyone has been
wondering what the future will be for our region
and for the world. We have witnessed studies put
on hold and budget-cutting everywhere. Of
course, this is a major concern for us and with it
comes the question, “Will Latin America continue
to be seen as a region of opportunity for the
global industry?” Will they (sponsors and CROs
in the Northern Hemisphere alike) capitalise on
the huge opportunities which are present here?
As members of the clinical research industry
in Latin America, we have the responsibility to do
our best to make this happen, to show the world
what we have done and are doing and, most
importantly, to demonstrate how well we are
performing. We must be proactive, have a strong
commitment and willingness to grow - we need
to actively pursue every chance to prove our
worth.
It is all too common to focus only our
industry of clinical research and not recognise
the impact that other industries have on our
success and learn from their actions how best to
approach such times as these. We need to take
a step back and adjust our objectives (both as
companies and as individuals) in order to make
them compatible with the realities of every
country. We must be self-evaluating. It is only
through a systematic review and enhancement
of our organisations that we will optimise our
resources. This is not the first economic
downturn experienced in recent years for Latin
America – let’s use our experiences of
overcoming adversity and adopt strategies
which have proved to be successful in the past!
Our region has been delivering first class
services and data to support new products being
brought into the market for many years now. We
have proven what we are capable of - and we
have handled - exponential growth. We should
act accordingly. Can we add real value? Of
course! Latin America is much more than a great
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cost-effective strategy to increase the number of
patients. We need to expand our focus to the full
reality that our services add much more to a
study’s success, in addition to patient
recruitment and monitoring.
Finally, we must promote to our national
governments the importance of the clinical
research industry for local economies. This goal
might seem too challenging, yet we have to face
it because we need our governments to support
growth and expansion of services long-term. We
should not approach this as if the only items on
our agenda are how to guarantee GCP
compliance and faster approval for studies. We
need them to strengthen the regulatory
framework in every country towards
harmonisation and predictability. And we must
collaboratively work with our governments to
discover opportunities for the common good. We
all know the definition of a vulnerable
population. It is obvious the financial situation
will likely have an impact on our local health
systems, medical institutions and, eventually,
patients. We should take this opportunity to
partner with our governments to discuss
priorities, providing sound metrics and
information to maximise transparency - ethical,
legal, and economic. National administrations
have a responsibility for the health of the
population, and this is our overriding
responsibility as well. We need to intensify our
ties and strategies to enhance the success. There
are ongoing efforts in several countries with
sponsors and CROs working together to collect
information. In fact, a few weeks ago the
Argentinean government created the first clinical
trial registry in the region, joining similar
initiatives from other countries. We do have
many common objectives and we should
encourage dialogue to work side by side to make
the most of this opportunity. I
Oscar Podestá is General Manager
for Chiltern, Latin America. Chiltern
was established in 1982, and is a
leading global Contract Research
Organisation
with
extensive
experience conducting and staffing
international Phase I to Phase IV
clinical trials across a broad range of therapeutic areas
for a wide variety of clients. Chiltern has conducted trials
in more than 40 countries and employs 1400 staff across
27 countries. Chiltern provides services including Early
Phase, Global Clinical Development, Late Phase,
Biometrics, Medical and Regulatory Affairs and
Resourcing Solutions.
E: [email protected] W: www.chiltern.com.
www.jforcs.com
PAEDIATRIC TRIALS – NOT
CHILD’S PLAY FOR INSURERS
It is common knowledge within the medical community that most drugs
prescribed for children have not been approved for use in minors. Effectively
they are being used in an off-label manner. This I am sure would surprise
the man in the street, and whilst the expression “off-label” when used in
medical circles is well understood not to mean inappropriate, improper or
even illegal use, it does send a message to the general public that
something is “wrong” and therefore the drugs may not be safe.
To prove a drug’s safety requires the type of human clinical trial
programme that drugs for general use are subjected to. Tests for safety,
efficacy, dosage and contraindications would be required. In an ideal
world, the assessment of a drug's effect on children would not be left to a
rough calculation of relative body weight or skin surface area, along with
empirical data from past years. However this has been the case until
recently.
This article will not drill deeply into the ethical issues surrounding clinical
trials on children, but as an underwriter asked to insure sponsors' legal
liability arising from such trials, it is important to be aware of these issues.
Ethical issues are legion and the unique manner in which paediatric trials
should be designed is legitimately part of the underwriting process.
The EU has recently adopted a kind of halfway house in its attitude to the
use of drugs on children. Accepting that an insistence of full separate
paediatric trials on all new medicinal products is impractical, the EMEA
introduced regulations stating that as of July 2008 marketing applications
for new products not authorised in the EU prior to 26 January 2007 had
to include the results of studies conducted in the paediatric population.
These studies have to be in compliance with an agreed Paediatric
Implementation Plan (PIP). The PIP is a development plan aimed at
ensuring that the necessary data is obtained through studies on children
(when safe) to support the authorisation of that medicine for children.
PUMAs (Paediatric Use Marketing Authorisations) were also let loose in
Europe, which enabled a medicine, already available on the market for
adults, to be approved for children following the completion of a PIP
agreed by the appropriate committee. There are various financial
incentives available to reward the effort made by companies acquiring
PUMAs.
So, with this regulation in place how do insurers go about assessing risks
in paediatric trials? First let’s define “Risk”: a good and succinct definition
is: “The potential harm (real or theoretical) or potential consequence of an
action”. Trials on children should be analysed for risks unique to the trial
population.
The foundation of everything must be the maxim that the child’s
interest should always prevail over that of science and society, and risks
must be set against the benefit that taking them might bring. It is the
responsibility of the sponsor and investigator to make an assessment of
the risks involved in a trial and to describe and explain this in the protocol,
thereby enabling the ethics committee to make an informed decision.
The risk assessment that insurers will undertake on the specifics of a
trial itself includes:
•
The evaluation of the medicinal product tested and if relevant
the control product
•
The risk of withholding active treatment where appropriate
•
The risk of the disease or condition being treated
•
The invasiveness or intrusiveness of the trial’s methodology
•
The reversibility of any adverse effect
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•
•
Age range of paediatric participants
Other trials on the same population leading to possibility of an
“overstudied” population
Insurers’ assessment of the way a trial is managed will include:
•
Clarity of protocol’s risk assessment (see above)
•
Number of sites involved and communication between them
(especially in multinational trials)
•
Age appropriate formulation (e.g. young children choking on
tablets) and the risk of dosing errors or inaccuracy
•
Informed consent documentation and process.
Informed consent is an ethical issue but also perhaps the most important
aspect for underwriters as it is, so to speak, where the trial and the subject
meet. Thus it is essential to have clear communication of information and
risk as insurers realise that participants’ knowledge of the risk can mitigate
the legal ramifications if litigation ensues. The latest version of the
Declaration of Helsinki suggests that for a legally incompetent minor, the
investigator must obtain informed consent from the child’s legally
authorised representative in accordance with applicable law. However a
“legally incompetent” minor may be able to give assent to decisions about
participation in research and in such cases the investigator must obtain
that assent in addition to the consent of a legally authorised
representative.
Of course the issue of childhood assent is contentious. An intellectual
age of seven years has arbitrarily been recommended for including children
in the assent process, but there is a body of professionals that consider
that children under 10 years old will not fully understand the complexities
of clinical trials and what they were being asked to assent to. Although
parents are expected to sign the consent documents, underwriters will look
to see that the child has been consulted to an appropriate level.
These issues aside, information sheets should be separate for parents
and children, should be concise in content, precise in language and age
appropriate. That said, the number of age-specific variations of consent
documents should be kept to a minimum, and the family as a whole should
be given sufficient time and information to consider the pros and cons of
their involvement.
Knowledgeable insurers operating in this area appreciate the increased
risks that are faced by all involved in this area of research. Premiums will
tend to be higher for paediatric than other trials as insurers are taking on
the risks of litigation following trials on children with the commensurately
higher award potential, but the EU Trials Directive (rightly) insists that
insurance be in place for all trials. Encouraging efforts have been made in
Europe and in the United States to address the myriad issues surrounding
paediatric trials. In the medical world it will require the combined efforts
of paediatricians, manufacturers, bio-ethicists, medical societies etc to
move the whole area of paediatric trials forward, and insurers, sharing in
the risks all involved face, must be aware and proactive in helping to assess
and mitigate risk in trial design, in addition, of course, to sharing in the
financial consequences of these risks. I
Chris Tait is the European Life Science Underwriting Manager for
Chubb Insurance Company of Europe SE. Over the last 30 years Chris
has gained a broad knowledge of the insurance industry. Chris has
been instrumental in developing Chubb's expertise in the Life Science
sector. He is a Chartered Insurer and Fellow of the Chartered Insurance
Institute. Email: [email protected]
www.jforcs.com
DIA EURO MEETING,
BERLIN 2009:
TAKEAWAYS FOR EMERGING
COUNTRIES’ CLINICAL TRIAL
CONDUCT
Venue
2009 marks the 20th anniversary of the fall of the Berlin Wall; this made
Berlin an appropriate setting for the 21st annual DIA Euro Meeting,
because the fall of the Berlin Wall heralding an age of improved East-West
dialogue and understanding was an excellent metaphor for the
deliberations and spirit at this recent DIA Meeting. The conference proceedings emphasised the ever more compelling need for affordable, safe,
efficacious and quality medicines to be made promptly available across
the world. There seemed to be universal recognition that countries in the
“East”, which include Latin America and Africa, represent both challenges
and opportunities as we endeavour to achieve safe, quick and affordable
medicine access. Hence there is an imperative for East-West dialogue and
co-operation which the Berlin Euro DIA Meeting facilitated in a stimulating
and enjoyable manner.
Attendees
Happily the constraints of the present financial climate did not dampen
attendance. There were over 1,600 attendees representing regulatory
agencies, pharmaceutical sponsors, vendors, academics, patient groups
and trade organisations. As has now become the norm, this DIA Euro
Meeting was attended by senior representatives from the EMEA and most
national regulatory bodies in Europe. In addition there was participation
from representatives of the US FDA, Japan’s PMDA, Europe’s key
pharmaceutical industry associations and patient groups. As a result
delegates were able to access the latest high-level industry information
and thinking; during formal presentations, audience discussion and via
informal networking. Further pharmaceutical companies, particularly most
of the leading ones and vendor organisations, were well represented. The
exhibit hall had an international flavour with exhibits of numerous
specialist CROs representing the emerging markets of India, Latin America
and Eastern Europe. Notably the Queensland Clinical Trial Network had an
exhibit to showcase the region’s considerable attractiveness for firstin-man clinical studies.
Plenary Session
The Architecture of the Future Governance System for Pharmaceutical
Products in Europe was the subject for the plenary session, organised as a
panel discussion, with panellists tasked with answering selected strategic
questions. Panellists included the leadership of regulatory agencies,
pharmaceutical companies and patient groups. The subjects discussed
were the evolution of the European Regulatory Network and the role of
National Competent Authorities, changing pharmacovigilance legislation,
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market access and pricing for new products and curbing the circulation of
counterfeit medicines. Although the discussion was Eurocentric with a focus
on Europe’s more developed pharmaceutical markets, each of the
panellists emphasised the imperative to provide widespread access to
affordable, safe and effective treatments. Clearly this imperative is a global
one and in spite of the huge disparity in per capita healthcare expenditure
between developed and emerging countries, the need for prompt access
to affordable, safe medicines able to treat unmet medical need is universal.
Panellists acknowledged the growing commercial value of emerging
markets, their potential to accelerate drug development and the threats
posed by fraudulent and poor quality practices.
Programme Overview
The main two-day conference programme was structured along 16
themes. Speakers with expertise in different functions representing key
stakeholders featured in the 6-8 sessions that addressed key questions
related to each of the themes. The programme structure was effective in
enabling attendees to fully explore themes of interest and listen to the
relevant perspectives. Not surprisingly difficult choices had to be made with
multiple sessions vying for attendance. Below is a selection of topics with
takeaways particularly relevant for emerging country clinical studies.
Audits and Inspections
This theme explored the evolution of Good Clinical Practice from
adherence to a rule book into a holistic working approach and most
recently to quality management. Inspections and audit have contributed,
and continue to contribute, to this evolution and should be carried out as
part of an ongoing quality management process. Experiences with
inspection of e-CRFs, e-source data and data analysis were shared along
with best practices for the delegation of sponsor functions to CROs and
other third parties.
A session describing experiences of European Competent Authorities
with the handling of serious GCP breaches and fraud provided useful
practical advice for industry, regulators, vendors and investigators. How
regulators obtain information about serious GCP breaches, including
falsification of data and fraud, was described. This was followed by a
delineation of sponsor, investigator and patient responsibilities with
recommendations on how to detect, report and avoid such cases. Issue
escalation and tools for quality and risk management remain important
and should be customised for an organisation’s needs.
To enable extrapolation of clinical trial data generated in emerging
countries for marketing authorisations in the USA and European Union
www.jforcs.com
(EU), there remains a strong need to harmonise quality standards across
geographies. This is particularly true given the different clinical trial
regulations in different countries and varying practices of GCP inspection.
Pharmacovigilance and Risk Assessment
Regulatory agencies face the challenge of balancing the facilitation of
early access to affordable medicines with the requirement for long-term
and thorough drug safety surveillance. Numerous initiatives including novel
pharmacometric techniques and the identification and qualification of
biomarkers are being undertaken to address this challenge. In addition
there is a growing regulatory dialogue exploring conditional approvals and
accelerated assessment with the definition of more specified treatment
criteria and narrower patient sub-populations; these refinements do have
implications for reimbursements.
Regulatory agencies in the EU have substantially increased their focus
on and investment in drug safety surveillance, both for their internal
processes and for industry supervision. Failure to comply with
pharmacovigilance regulations could result in seriously negative legal,
regulatory and media consequences for the sponsor. Regulatory agencies
have, or are soon to adopt, intelligent data mining tools for proactive and
systematic oversight of pharmacovigilance
processes and adverse event data. As regulators
in India, China and Russia seek to strengthen
their respective drug safety surveillance
processes; there is a compelling opportunity for
learning from and sharing best practices with the
more experienced regulators. The opening of
FDA offices in India and China and the EMEA’s
investment in an international liaison function
indicate that regulators on both sides recognise
the need for enhanced co-operation.
Furthermore the FDA and regulatory
agencies in Europe more frequently need to
evaluate marketing authorisation applications
which include pivotal studies with an increasing
proportion of subjects enrolled in emerging
countries. Ensuring that these data have the
quality, scientific applicability and ethical
integrity represents additional regulatory
responsibility.
Paediatric drug development statements have been obligatory for
marketing authorisation in the EU since January 2007. However practical
issues regarding consent, recruitment, patient referrals and granting of
waivers remain to be fully addressed. Further the ethics of conducting
clinical research in a paediatric population are far from clear.
Unusual trial designs that were discussed included an open, nonblinded clinical trial initiated by a patient group and driven by a steering
committee with representation from participating patients. Following the
unfortunate TGN 1412 experience standards for first-in-man studies for
biologicals has substantially evolved. Emerging country CROs seeking to
offer services in this segment are advised to understand this.
Recent financial constraints in the global business environment have
accelerated the rationalisation and consolidation of R&D departments
within large pharmaceutical companies. The sale of Lilly’s pre-clinical
research facility to Covance last summer remains a notable example of
sponsor companies seeking to reduce their fixed R&D costs by forming
strategic relationships with CROs. This has accelerated the trend for
increased and more sophisticated utilisation of CROs with a move from
transactional contracts that meet the sponsor’s short-term resourcing
requirements to partnership based strategic outsourcing. Although small
to mid-sized sponsors continue to utilise CRO
services in a tactical, project-driven fashion, it
is expected that soon they too will increase the
breadth and depth of their CRO utilisation.
“Unusual trial designs
that were discussed
included an open,
non-blinded clinical trial
initiated by a patient
group and driven by a
steering committee with
representation from
participating patients.”
Increasing Clinical Trial Complexity
Ken Getz, Senior Research Fellow from the Tufts Centre for the Study of
Drug Development, Tufts University presented an analysis of 10,000
clinical trial protocols conducted between 1999 and 2006 to demonstrate
that the complexity of clinical trial design has sharply increased. The
number of unique procedures and the frequency of these procedures per
protocol have increased at the rates of 6.5% and 8.7% per year,
respectively. Protocol eligibility criteria have increased by over 12% per
year and the administrative burden on investigative sites has increased by
an estimated 10.5%. Furthermore, the number of protocol amendments,
observed serious adverse events and length of the case report forms have
all substantially increased. He recommended that sponsors develop
processes to examine and limit protocol complexity, citing examples of
initiatives undertaken by Genentech and Pfizer.
Some of the drivers of clinical trial complexity are expanding global
reach, adoption of novel technologies, increasing utilisation of patient
reported outcomes (PROs) and the requirement to conduct paediatric
studies.
Best practices for the integration of PROs into the different stages of
drug development and lifecycle management were shared; along with the
use of electronic PROs and their acceptance by regulatory agencies.
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Clinical Trials in Non-ICH Countries
A well-attended session discussing the
implementation of ICH in non-ICH countries
highlighted the increasing utilisation of
emerging countries for global clinical
development. The aims of harmonisation are
to avoid duplication of clinical trials and to
enable early access to new treatments. There
remain strong ethical and economic reasons to
avoid unneeded repetition within or
prolongation of the clinical trial process. In
order to achieve this, regulatory agencies
worldwide should be able to extrapolate clinical
trial results accrued from non-ICH countries.
The ICH regions are the USA, EU and Japan;
with the growth in emerging country clinical trial activity, harmonisation
between ICH and non-ICH countries is becoming increasingly
urgent.
Dr Nermeen Varawalla, President, ECCRO described the Ethical and
Scientific standards of ICH; namely, the protection of the rights, safety
and wellbeing of trial subjects, and obtaining credible trial data
acceptable by other regulatory authorities, respectively. A number of issues
remain for emerging countries to fully meet these ICH standards.
Socio-economic inequity, unmet medical need, cultural and linguistic
variability and post-trial access are some of the issues that need to be
addressed for the ethical standard to be met. Whilst the inexperienced
clinical trial environment, nascent regulatory structures, unanswered
scientific questions and variation in standards of care are factors that could
influence meeting of the scientific standard.
Kohei Wada, Co-Chair of the ICH Global Co-operation Group (GCG)
described the group’s role to promote better understanding of ICH and its
guidelines, by information sharing via brochures, websites and
presentations at international meetings. More recently their remit has
expanded to include facilitation of capacity building in non-ICH countries;
within the industry and at regulatory agencies. The training of regulators
and industry representatives continues to be a high priority; this is being
achieved by frequently held and increasingly well attended workshops
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located in various emerging countries. He stressed the importance of a
collective effort with a spirit of co-operation.
Fergus Sweeney, Inspector, EMEA clarified that when assessing a
marketing authorisation application, regulators do not place limits on the
proportion of data accrued from a particular region; provided that the
clinical data meets the quality, regulatory and ethical standards of that
regulatory agency. Examples were cited, where for appropriate indications
for example in a vaccine study, all the clinical trial data was accrued from
emerging countries.
Public Perception of Pharmaceutical Research
There has been an erosion of public trust in pharmaceutical research with
a tarnishing of the image of researchers, the industry and regulators. There
was consensus that transparency about the methodology and results of
drug research was the way forward to build public trust. Clinical trial
registries, publication of trial results, public access to clinical trial data, clear
definition of commercially sensitive information, elimination of ghost
writing and full disclosure of funding arrangements between industry and
researchers were all essential to create this transparency.
The media has contributed to public mistrust and could potentially help
reverse this. Speakers and members of the audiences voiced their views on
how researchers, the industry, legislators and regulators can better work
with the media, so that it can progress from being sensationalist and
alarmist to providing society with a fair, more accurate picture of the drug
discovery and development process. The Indian press was cited as an
example of the media playing the role of a watchdog, protecting the
exploitation of the lay public; by monitoring practices of the industry,
clinical institutions and the Drugs Controller General of India. Although this
is yet to build public trust it has succeeded in making industry and
legislators more accountable.
This theme also looked at the challenge of patient education and
communication; recognising the advantages of a better-informed patient
community able to understand the benefit-risk equation that is inherent
in pharmaceutical research and usage of medicines. Educating patients to
absorb and understand both the risks and effects of medicines remains
complicated with significant cost implications. But engaging the users of
medication is essential in order to achieve the goal of early affordable
access to new medications.
Finally a session examined the dilemmas of improving the informed
consent process for clinical trial participants; seeking to find a balance
between long and jargon-rich patient information sheets and effective
communication able to fulfil ethical requirements. Results of a recent UK
survey were disappointing, indicating that an alarmingly low proportion of
clinical trial participants understood the main points of the informed
consent materials.
The discussion points of the public perception theme are a great
example of how some of the most critical issues affecting pharmaceutical
research are truly global in that they remain equally applicable in both the
developed and emerging clinical trial settings.
Adaptive Trial Design
Adaptive or flexible trial designs allow for re-designing the study based on
the results of interim analyses, by altering, for example, sample size, the
randomisation ratio or the number of treatment arms. The statistical
theory underlying these trial designs along with software tools allows for
precisely controlling the type 1 error probability and hence the significance
levels. The benefits of such a trial design could be acceleration of the
clinical trial process, enhancement of trial efficiency and improved patient
safety. Practitioners continue to await integrated tools and processes for
patient allocation, drug supply management, clinical data management,
study resource planning and practicalities of statistical analysis. The
regulatory perspective on midstream adaptations of a clinical study is
24 JCS
discussed in EMEA’s Reflection Paper, 2007 and FDA’s draft guidance, 2009.
Importance of Health Economics
The worldwide healthcare budgetary constraints could limit market access
of new products and technologies. Health economics has the potential to
help achieve the goal of sustainable and equitable access to biomedical
innovation for all global societies. A decade after the formation of NICE in
the UK, almost all EU countries have established processes and
standards for Health Technology Assessments and economic appraisal.
Evidence of product value is needed to satisfy questions posed by
reimbursement agencies, clinical guideline committees, prescribing
physicians and self-paying patients. Thus endpoints able to demonstrate
product value have become essential clinical trial objectives alongside
those for safety, efficacy and quality. Furthermore product value data can
have a profound influence on product pricing. PROs are increasingly used
to capture the patient’s view and experience regarding the value that they
perceive they have received from the product. Also post-marketing data
from patient registries and observational trials has an important role.
Health economic analysis has been particularly relevant for facilitating the
launch of orphan drugs.
Extrapolation of health economic data from emerging country clinical
trials is difficult given the variation in standard of care and patient
expectations.
Personalised Medicine
The holy grail of the discipline of personalised medicine is to deliver
targeted, individualised medicines with improved efficacy, safety and
value. Better understanding of individual responses to disease and disease
response to a particular drug; namely, prognosis and prediction,
respectively, remain the foundation for personalised medicine. The
integration of biomarkers into the clinical process, clinical validation of
biomarkers, health economic outcome evaluation, benefit-risk assessment
and co-development of drug-diagnostic combinations are some of the key
tools and techniques that are being actively explored. This is a discipline
with much promise, hence one to watch.
Continuing the Dialogue
The 21st DIA EuroMeeting successfully showcased the latest thinking
across many key areas affecting the development and use of medicines.
The forthcoming annual DIA Meeting in San Diego, which is expected to
attract many more worldwide attendees, with a greater proportion
engaged in emerging country clinical development, will no doubt provide
an opportunity to re-visit some of these themes with a US-centric and
global perspective. The 3rd Annual DIA Clinical Forum to be held in Nice
in October this year will bring together the disciplines of clinical data
management, validation and statistics with clinical trial operations to
encourage cross-functional dialogue and closer collaboration. The
programme highlights a strong focus on sharing experiences, case studies
and best practices.
Readers are encouraged to attend both meetings, and if unable to do
so, they should look out for coverage of these and other key industry
meetings in forthcoming issues of Journal for Clinical Studies; the
industry’s only publication focused on emerging country clinical trials. I
Dr Nermeen Y. Varawalla, MD, DPhil (Oxon), MBA recognised to be
an industry expert in the utilisation of emerging countries for global
clinical trials and leads ECCRO – the pan Emerging Country Contract
Research Organisation. She was awarded the Rhodes Research
Fellowship to the University of Oxford where she conducted her
doctoral research in Molecular Genetics. In recognition of her expertise
in the globalisation of clinical trials, Dr Varawalla is frequently invited
to speak at industry conferences. In addition she is a regular
contributor to industry trade and peer reviewed publications and serves on the editorial
board of the Journal of the Institute of Clinical Research, India and the Journal for Clinical
Studies, UK. Email: [email protected]
www.jforcs.com
ESTABLISHING OF INFRASTRUCTURE FOR
ETHICAL REVIEW IN KAZAKHSTAN
Modern development of science and technology is typically accompanied
with increased public attention to ethical and legal aspects of scientific
research. There is a systematic implementation of ethical principles in
Kazakhstan.
Regulatory framework
Kazakhstan citizens still do not have an important legal instrument to
protect their rights in the increasingly important area of application of modern
biotechnology.
Kazakhstan Constitution Article 29 notes: Citizens have the right to
healthcare; have the right to free and guaranteed medical care; Paid
medical care at state and private medical facilities as well as from persons
engaged in private medical practice shall be rendered in the terms and
procedures. Article 31 goes on to note; Suppression of facts and
circumstances endangering people’s life and health by officials shall bring
about responsibility as provided by the law. Article 39 states; the rights and
liberties of man and citizen can be limited only by laws and only to the
extent necessary to protect the constitutional system, maintenance of
public order, rights and liberties of man, health and good morals of the
population.
In addition, Law No. 170 ‘Health Protection of Citizens in the Republic of
Kazakhstan’, provides for the procedure of application of new
prevention techniques, diagnostics, medications, immuno-biological drugs,
disinfectants, biomedical research, preclinical research, medical and
biological testing, clinical studies, application of new techniques and
methods of prevention, treatment and rehabilitation.
●
Preclinical research… shall be conducted on animals.
●
Clinical tests on humans may be conducted only upon receipt
of his written consent thereto… Clinical testing shall be
terminated at any stage thereof at request of the person under
test as well as in cases of a threat to his life and/or health.
●
Application of new methods and preventive measures,
diagnostics and medical rehabilitation shall be possible upon
positive results of clinical studies.
Conclusion
The principle of voluntary and informed consent has been legally set forth.
This article of law is pretty much declarative, and although some rights of citizens taking part in biomedical research are established, it does not
contain any enforcement and remedy mechanisms. Nothing is provided in
terms of necessary preliminary ethical evaluation of research
applications.
RK Law No. 522-2 ‘On Drugs’ (2004) details the regulation of testing of
new medications;
●
The aim of the clinical studies and testing of pharmaceuticals
is to evaluate and prove, using scientific methods, that such
pharmaceuticals and medications are safe and effective.
●
Decisions on clinical studies and testing of pharmaceuticals
shall be made by the state authority.
●
A written consent shall be taken from the voluntary participants of
clinical studies and/or testing of pharmaceuticals.
●
Prior to clinical studies, the patient shall be provided with
information on: i) the medication; ii) safety, effectiveness and risks
to health; iii) actions in case of unforeseen health events; iv) terms
and conditions of his health insurance.
●
The patient has a right to refuse to participate in clinical studies
and/or testing of a pharmaceutical or medication at any stage of
the testing.
26 JCS
●
It is prohibited to conduct clinical studies and/or testing of
pharmaceuticals and medications on: i) children up to 16 years
old; ii) pregnant women; iii) military personnel; iv) persons serving
sentences in detention centres and persons at pretrial detention
centres; v) persons recognized as disabled.
Unless the medical products concerned are only intended for the
above-mentioned groups.
This law has been drafted based on the assumption that ethics committee
expertise shall precede each testing. However, the status of an ethics
committee, its authorities, its establishment and the composition of the ethics
committee are not defined in the law.
Although constantly violated, this article includes a statement that children
under 16 may not participate in testing of new medication, treatment methods.
It should be noted that contemporary international norms allow testing
involving children and other vulnerable groups provided that certain clearly
defined terms have been met.
Instruction on Clinical Studies &Testing of Pharmaceuticals and
Medications in the Republic of Kazakhstan, as approved in 2005; Instruction
was adopted in addition to the Law.
•
•
•
•
Attachment 4 – Instruction on Cooperation with the Commission
on Ethics and Ethical Evaluation of Clinical Studies.
Attachment 5 – Application for Ethical Evaluation of Materials of
Clinical Testing.
Attachment 6 – Opinion of the Commission on Ethics Re: Results of
the Ethical Evaluation of the Materials of Clinical Testing.
Attachment 11 – Instruction on Provision of the Person Under Test
with Information on the Clinical Study and Receipt of a Written
Informed Consent from Him.
At the same time ‘Good Clinical Practice’ (2006), the departmental regulative
act representing the standard of the RK branch, has been developed. It set forth
obligations of all the parties involved in the research, as well as the procedure
and activities of ethics committees during studying of the effects of a
medication on human subjects.
Today biomedical research has actually become a whole industry in which
the interests of various parties intersect and often come into conflict. The
absence of due legislation does not allow protection of persons bring tested,
while the absence of legislation makes the status of all other persons involved
insecure. Further, it appears as if Kazakhstan does not have a reliable legislative
barrier against the “import” of such research that might be dangerous to our
citizens. The absence of developed structures and tools of ethical expertise
obstructs the promotion of local biomedical achievements to the world
market.
To date there is no clear system to regulate ethics committees that conduct
ethical expertise of any research involving human subjects.
Although, Ministry of Health Care has initiated the establishment of a
Central Ethics Commission at the MoH, and local ethics committees at all
scientific institutions under the MoH administration, to carry out clinical studies
for ethical expertise of the research involving humans. I
Prof. Bakhyt Sarymsakova MD, PhD. Position: Head of
Department of International Cooperation, Astana Medical
University. Prof. Sarymsakova is Executive Secretary of National
Ethics Committee and has been working in public health sector for
many years. Research interests are in bioethics and public health.
She served as a PI for several projects with COHRED (Geneva),
AHPSR (WHO), UNESCO. Email: [email protected]
www.jforcs.com
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INTERVIEW:
INVESTIGATING THE
RUSSIAN AND EASTERN
EUROPEAN CLINICAL TRIAL
MARKETS
1. Let us start with a little bit about Congenix. What are your
company’s special features? What is your present position in the
market? What countries of the CIS region does your CRO work in?
Congenix was established in 2004. Before the company’s creation its
founders spent years working at different CROs, both international and
local, and also in the Ministry of Health of Russia. This background has
allowed us to form our own vision of what is necessary to begin. As
opposed to the majority of companies which are represented in the
market, we have invested time and funds in the installation of quality
systems. We would like to express our gratitude to Quality and Compliance
Consulting, Inc. and Verdandi AG for their help in this. The results of
independent audits have completely proved the benefits of such an
approach. Besides, compliance with high quality standards is one of the
important factors helping us to successfully win tenders. For example, in
2008 Congenix won the right to organise and conduct a big 600-patient
clinical trial sponsored by a pharmaceutical company which is a member
of the top 5.
Since all Congenix staff involved in projects have a medical education,
Congenix does not have any therapeutic specialisation. We have
knowledge and experience wide enough to start a project from the zero
point, for example in both cardiology and in oncology.
At the same time we are quite flexible, and the reason is that the
company is managed by its founders, who are directly interested in results.
All important decisions can be made easily without loss of time.
Often we organise and conduct the local part of a clinical trial as a
sub-contractor for other middle size CROs. With one such company we have
a long partnership, and altogether our companies are able to conduct
projects in most parts of Eastern and Central Europe. At the same time we
also hope to appear in the US market through developing partnership with
one of the leading American CROs. This company is the pioneer in
conducting adaptive clinical trials. Its unique technology is designed to
save time, reduce costs and provide real-time information and decisionmaking capability for the sponsors.
In spite of the fact that we mainly have experience in conducting Phase
I/II and II clinical trials, it should be pointed out that Congenix also has its
own resources, including human resources, to conduct an international
multicentre Phase III project.
To sum up, Congenix is not a big company, but we have experience,
wide opportunities and flexible approaches which allow us to successfully
operate as an expert CRO in our geographic area.
2. What are the most common challenges faced by a CRO like yours
in its respective regions?
We would like to highlight the widespread points to be considered before
28 JCS
setting up a clinical trial in Russia and the countries of Eastern Europe:
regulatory details; staff availability; availability of comparator; standard
therapies; validation of study tools, e.g. patient questionnaires; laboratory
samples logistics; communication and language barriers.
First of all we would like to highlight briefly the regulatory details in
Russia and some countries of the CIS where we operate.
The legal basis to conduct clinical trials in Russia is the 1998 Federal
Law on Drugs. The regulatory basis for conducting clinical trials in Russia is
the 2005 National Standard of the Russian Federation 52379-2005 Good
Clinical Practice, a translation of the GCP E6 guideline. The Russian Ministry
of Health and Social Development also regulates the process by means of
various Orders and Instructions, all of which have been developed in
correspondence with the law and national standards.
The next promising country for conducting clinical trials is Ukraine.
Clinical trials are regulated here by state law ‘On medicinal products’,
effective from 1996, and the regulations approved by the Ukrainian
Ministry of Health in 2006. The latest documents were developed taking
into consideration the requirements of Directive 2001/20/EC.
At present, a regulatory basis is being formed in Kazakhstan for the
clinical research market in this country. The following local laws are
applicable for conducting clinical trials: instruction for conducting the
clinical trials approved by Ministry of Health of Kazakhstan in 2005; Drug
Law approved in 2004.
The law regarding approval of clinical trials in Byelorussia became
effective in 1993. The revision of regulations for conducting clinical trials
is ongoing in Byelorussia. The role of local ethics committees is very
important, and informal, international insurance is accepted in this country.
In Moldova the approval process for clinical trials is regulated by the
drug law about pharmaceutical activities, effective from 1997, and the law
about rights and responsibilities of subjects effective from 2005 in parallel
with international regulations.
Thus the main countries with significant recruitment potential have
structured and well organised permit systems and regulations which satisfy
the requirements of ICH GCP guidance.
Concerning the availability of study staff, it is necessary to note that
Russia ranks highly among other Eastern European countries in the
availability of basic medical resources for conducting clinical trials. At
present, most clinical trial work is conducted in Moscow and St. Petersburg
owing to the better infrastructure, large populations and the presence of
major research centres in these two cities; the well-equipped academic sites
located to the east - from the Ural Mountains in Siberia to the Far East, which
is rich in natural gas and oil resources - remain largely underused. While many
medical procedures that in the West might be performed in an outpatient
setting, in Russia call for a stay in hospital, hospital costs do not add
www.jforcs.com
Great Bridge of St Petersburg, Russia
significantly to the trial expenses. Moreover, this additional level of attention
is helpful in informing the subjects of their obligations and providing the
opportunity to closely monitor and instruct them early on, thus helping to
facilitate compliance. At the same time we meet situations when the
comparator(s) are not available at the clinical sites or the standards of
treatment are significantly different from what is conventional in Western
countries. This is a so called “fly in the ointment” decreasing the number of
trials which could be potentially conducted in Russia and the countries of
Eastern Europe.
We also would like to touch briefly upon the issue of laboratory samples
logistics.
During the study course all laboratory samples run freely between study
sites and central labs. All the main international courier companies are
present in our region. In some cases we prefer to use the local courier
companies since they are more flexible and able to perform difficult tasks.
But sometimes unexpected events can happen. For example, a ban on the
export of biological samples which lasted for two weeks in June 2007
impacted on clinical trials conducted in Russia, despite its brevity. This fact
led to a decrease in the numbers of international clinical trials conducted in
Russia compared to the second quarter of 2006. At the same time this event
highlighted the opportunities for local laboratories to serve as central
laboratories. Our company has a very positive experience working with the
laboratory INVITRO.
Communication lines are also very important. We understand that our
company is not positioned in a closed space, but is in close connection with
the sponsor and local regulatory bodies, as well as with the clinical site’s
study team. It is not a secret that clinical trials are not the main activity for
physicians. And sometimes our company faces a challenge when the
investigator and his/her study team do not give enough attention to the trial.
In this situation only close interaction between the CRO and the site study
team, and competent site management, help to resolve the issue.
Concerning the communications with competent and expert bodies, our
company also prefers an active position. Practice has shown that the CRO
should be not only an intermediate link between competent authorities and
the sponsor, but also should be actively involved, for example, in the
discussion process at the stage of obtaining clinical trial authorisation. For
example, the involvement of our regulatory experts has led to a positive
outcome, an exit from no-win and obtaining clinical trial authorisation for
an early phase clinical trial dedicated to treatment of rheumatoid arthritis.
3. What strategies have you put into place to improve the quality and
safety of the clinical trials in the CIS regions?
We would like to note that quality management is the key component of
our work, as well as compliance with all applicable regulations.
It is critical that our project managers develop a QC plan for each
significant operational stage of the study, including investigator selection
and qualifications; study monitoring and source documents verification;
query resolution, etc.
Congenix establishes annually an audit program to verify conformance
to contractual requirements, sponsor needs, contractual obligations and
regulations, to obtain and maintain confidence in its capability to deliver
quality services and to improve existing processes.
The Congenix QA department performs trial-specific audits to evaluate
30 JCS
the trial conduct and compliance with the protocol, SOPs, GCP and
applicable regulatory requirements. Depending on the audit type,
trial-related audits may be conducted at Congenix, investigator sites
managed by Congenix or other locations.
Our QA department also performs system audits to assess strengths,
deficiencies, weaknesses and areas of potential improvement of systems
related to the conduct of clinical trials.
We strive to continuously improve the quality of the services provided to
sponsors. Congenix welcomes suggestions for improvement, in particular
feedback from audits, e.g. in formal audit reports or discussion with QA
auditors.
4. Could you please give us an example of best practices of ethical
review in the region?
Since the clinical trial approval system in Russia is well developed, the
central ethics’ committee review is very likely an example of best practices.
The process of obtaining the approval of the regulatory authorities for
clinical trials in Russia much improved in 2008. The work of the Central Ethics
Committee was reorganised in the last year and the process now flows faster.
An Ethics Committee provides us with its final approval within two weeks. In
the height of summer we submitted documents for one of the
projects, they were reviewed in the next meeting of the Central Ethics
Committee four working days later and received final approval in less than
one week.
5. What kind of educational programmes do you have which can be
offered to the sites?
Congenix provides investigators with its own developed training which gives
an idea of the drug development process and describes all investigator
responsibilities in the course of a clinical trial. In particular, we recommend
this training for investigators who are only starting to work in the area of
international clinical trials.
6. What is your vision for the future and where do you see Congenix in
the next five years?
From our point of view the company’s success will be based on the
following key elements: the maintenance of the company’s flexibility;
Congenix’s strengthening in our geographic region; acceleration of our
business development efforts; and taking on board the new unique services
which will significantly single us out among the others.
Without any doubt Congenix will remain the foremost reliable and
client-oriented company providing professional services in the field of
clinical trials. I
Irina Dobreva is Chief Executive Officer and co-founder of
Congenix LLC, a Russian CRO established in 2004. Irina has
extensive experience in clinical trials, not least starting as an expert
at the Russian Ministry of Health. She qualified in Medicine from
Ural State Medical University and trained in Oncology.
Email: [email protected]
Dr Vladimir Novakovskiy is Managing Director, Clinical
Operations and Regulatory Affairs at Congenix. Dr Novakovskiy holds
a medical degree from St Petersburg Medical University. He has also
got a PhD in medicine, specialising in oncology and immunology.
Email: [email protected]
www.jforcs.com
UNDERSTANDING AND
ADDRESSING THE UNIQUE
CHALLENGES OF CLINICAL
TRIALS IN THE SUPPORTIVE
CARE OF CANCER PATIENTS
It has been widely reported that only 2 to 4 per cent of new adult cancer
patients in the United States participate in clinical trials. Representation
is known to be especially low from elderly and minority populations.1,2,3
Data from the National Cancer Institute reveal that 1.4 million Americans
received a diagnosis of cancer in the 12-month period from January
through December 2006 (most recent data available).4 That number will
be higher for 2008. Given those statistics, one could reasonably estimate
that in 2008, only 48,000 to 50,000 patients will participate in the
thousands of cancer trials open to enrolment in the United States. A small
portion of those will consent to participate in a supportive care trial. We
can take steps to improve the rates of enrolment into cancer trials overall
and supportive care trials in particular.
Researchers supported by government, academia and industry work
diligently to develop safe and effective medicines to prevent and treat
cancer, and to ameliorate side-effects of treatment. Although there are
many research objectives, the primary goals are to increase survival,
decrease side-effects, and maintain or recapture quality-of-life for cancer
patients in all stages of their disease and treatment. Pre-clinical and clinical
trials are on the critical pathway to conquering cancer, and patient
volunteers are required to win that fight.
The NCI, which sponsors more than 8,000 active trials as of this writing,
reports that less than 2 per cent of the adults diagnosed with cancer in the
United States each year receive treatment through enrolment in an NCI
Cooperative Group clinical trial.5,6 That means that only another 1 per cent
(~16,000 patients) of those newly diagnosed are enrolled in trials outside
of the NCI purview. The low rate of clinical trial participation lengthens
the time required to meet patient accrual targets for trials and therefore
lengthens the time required to complete clinical trials, slowing the pace of
progress in improving cancer treatments.
Every cancer patient is a potential subject in a clinical trial. But where
do the volunteers come from? Which patients tend to be enrolled in clinical
trials and which populations do not? And why? Researchers from
University of Wisconsin reported in May 2008 at the American Society of
Clinical Oncologists that data from a 1900 patient study revealed that
60% of newly diagnosed cancer patients say they were never told of trial
options.7 The same report also indicates that patients satisfied with care
are more likely to enroll in trials and that patients in rural settings and those
involved in support groups and even those who travel relatively far
distances to receive care are more likely to enroll. In 2002, researchers
from UC Davis Cancer Center reported a much higher rate of trial
participation than the average. They defined five broad categories of
potential barriers to participation, including lack of resources on the part
of the patients; health insurance restrictions; confusion about the
differences between research and medical care; confusion about the
procedures of the trial itself; and misunderstandings about the illness and
its severity.
www.jforcs.com
Those patients who do volunteer to participate in a clinical study do so,
perhaps, for very different reasons. Even within a single individual, the
decision to volunteer or not may change several times over the course of
his or her post-diagnosis lifetime. Careful consideration of the various
motivations and deterrents to clinical trial involvement of the cancer
patient is critical to the success of any clinical trial in this arena.
Treatment trials are often more attractive to both investigators and to
their patients, and the reasons are obvious – patients and their physicians
will go to extremes to preserve life. It follows that, if enrolling patients into
treatment trials is difficult, enrolling patients into trials designed as
supportive care is often many times more arduous. Consider the choice
of enrolling in a trial to treat your cancer or to treat the side-effects of your
life-saving treatment - nausea, neuropathy, anemia, or depression. Which
would you choose? Would your choice change under varying
circumstances?
Consider the overwhelming odds against a patient even finding a
supportive care trial when NCI posts 29 trial results in supportive care while
listing more than 8,000 NCI-supported treatment trials.
Enrolling patients into any particular clinical trial is difficult, especially
in the regions of the world where healthcare is relatively available, options
for treatment are many, and there are many clinical trials open to
enrolment at any given time. To anyone working in the universe of clinical
research today, it is evident that:
•
the number of trials seeking to enroll volunteers with
cancer is huge and on the rise;
•
the competition for patient-volunteers is increasing;
•
patients may be presented with many potential
trial choices or may not know of a single one;
•
the importance of clinical trial participation is not
well-known in the population;
•
patients are fearful about trial participation;
•
the need to seek clinical trial subjects in other parts
of the world continues to be important and
increasingly so;
•
information is increasingly available to patients via
the internet and patients are, therefore, capable of
becoming very well-informed regarding their
treatment options and the trials seeking enrolment;
•
communities of patients, both real and virtual, are
powerful forces for support, communication, and
influence; they can drive patients to trials or away
from them.
The keys to success in enrolling into any clinical trial include:
•
a feasible protocol;
•
committed physicians and study coordinators
experienced in clinical research;
JCS 31
•
•
•
•
patient education and outreach;
appropriate educational materials;
advertising and trial awareness campaigns
including trial branding and promotion;
MD-to-MD outreach involving other community
physicians outside the trial construct.
critical. Appropriate materials in cancer clinics and on the web can
engender conversation and increase comfort in the clinical trial option. The
altruistic act of trial participation is highly motivating for some patients
but requires understanding and support of their family and support
network.
How then can the important clinical trials of therapies used to treat the
side-effects of chemotherapy - the supportive care trials - enroll the
subjects required? The universe of potential subjects is large; the
participation of adults is small; the preference for participation in a
treatment trial is often overwhelming. Can clinical trials in supportive care
be done within reasonable timeframes? What does including ex-US sites
add to the mix, and why?
Cancer-community involvement and support.
Investigators can do only so much. They can speak to patients as they
return to the clinic for treatment and suggest clinical trial participation at
that time. They can mount a call-out to qualifying patients in their practice.
But better still is to have the community of cancer patients at large (or the
community of a specific diagnostic subgroup) drive conversation and
consideration of trials from the patients (the many) to the investigators
(the relative few). Industry support in the community forums is critical
here.
The keys to enrolling subjects into supportive care trials include all of the
above AND:
Where possible, trial design should facilitate the enrolment of
patients whose treatment regimens are already defined and include
current, approved therapies.
The advantage to participation in a supportive care study is to optimise
treatment, whether in increasing a patient’s ability to tolerate the sideeffects of their treatment, thus allowing them to complete their scheduled
regimen, or to allow them to maintain a higher quality-of-life while
undergoing treatment.
Inclusion of a large number of sites in the trial.
Given the unique challenges to enrolment, trials in the supportive care area
will likely require more study centres than might reasonably be estimated.
Although many patients may qualify for entry, and although the
population at a study site may appear to be more than adequate,
enrolment goals will only be met with a very large number of approaches
to patients – many patients and perhaps several approaches over the
course of treatment.
Selection of Principal Investigators and study centres with a focus
on community, patients, and even supportive care and an
understanding of the barriers to enrolment.
Smaller, community-based, rural practices may be the ideal, as they pull
patients from a large area to a centralised, focused community practice.
Patients feel comfortable and participatory, and not lost in a huge
bureaucracy. Investigators who are highly involved in their community
and whose patient population is drawn from a large area have been very
successful in past trials. A patient might travel monthly to New York City
for cutting-edge treatment of their disease, but they are less likely to do
so as required for a supportive care trial. Education and outreach to
minority and elderly patients can increase participation into the trial.
Careful and considerate timing of the request of a patient to
consider a supportive care trial.
Has the patient chosen a standard of care treatment option to which a
supportive care trial could be adjunct? Does the patient understand the
benefits of ameliorating side-effects so that chemotherapy regimens
might be continued without suspension? Or, is the patient seeking ‘cutting
edge’ experimental treatment for their disease in a clinical trial setting?
The latter would preclude many other supportive care trial options.
Repeated approaches to patients discussing trial considerations
during the course of their chemotherapy treatment.
Patients who may be willing to volunteer may be interested in a trial after
their first course of chemotherapy once they understand what is going to
happen to them in the administration of a cycle of their treatment.
Patients may be willing to participate in a supportive trial if they have
chosen a standard-of-care treatment regimen with their physicians.
Patients may choose a supportive care trial when they are being treated for
recurrence of their disease rather than when receiving first-line therapy.
Family and caregiver education.
Families are hugely influential in the patient decision-making process and
many decisions are required of the cancer patient. An understanding of
the clinical trial process, trial options, and human subject protections, is
32 JCS
Adding sites outside of the United States.
Ideally, the volunteer rate for patients into clinical trials will increase over
time in the US. However, it is increasingly important to expand the search
for qualified and interested subjects into other parts of the world. Much
success has been documented in the conduct of clinical trials in emerging
markets, where patients benefit greatly from the basic care provided in
any trial – treatment or supportive care – and their choice of either one
has an important and positive outcome in the healthcare they receive.
Those of us in the business of clinical research and, specifically, those
conducting trials in supportive cancer care need to work to deliver all of
the requirements for trial success in the supportive care arena, if we are to
adequately serve the growing population of cancer patients through
cancer trials in the coming years. I
References:
1. Joseph R. Viewpoints and concerns of a clinical trial participant. Cancer. 1994;74:2692–2693.
2. Trimble EL, Carter CL, Cain D, Freidlin B, Ungerleider RS, Friedman MA. Representation of older
patients in cancer treatment trials. Cancer. 1994;74(7 suppl):2208–2214.
3. Kaluzny A, Brawley O, Garson-Angert D, et al. Assuring access to state-of-the-art care for U.S. minority
populations: the first 2 years of the Minority-Based Community Clinical Oncology Program. J Natl
Cancer Inst. 1993;85: 1945–1950.
4. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L,
Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics
Review, 1975-2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006/,
based on November 2008 SEER data submission, posted to the SEER web site, 2009.
5. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: Race-, Sex-, and Age-Based
Disparities. Journal of the American Medical Association 2004;291:2720-2726. [Abstract] Last
accessed July 6, 2005.
6. Christian MC, Trimble EL. Increasing participation of physicians and patients from underrepresented
racial and ethnic groups in National Cancer Institute-sponsored clinical trials. Cancer Epidemiology,
Biomarkers & Prevention 2003 (suppl.):12:277s-283s. [Abstract] Last accessed July 6, 2005.
7. Wassenaar TR, Walsh MC, Cleary JF, Remington PL and Trentham Dietz, A. Journal of Clinical
Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20
Supplement), 2008: 9524
8. UC Davis News Release May 20, 2002
Donna E Beardsworth is the founder and Chief
delivery Officer of Beardsworth Consulting Group, Inc
and currently serves as the Chief Delivery Officer for
the organisation. Beardsworth is a full-service CRO
with a 23-year history of delivering quality clinical
research projects. Beardsworth specialises in the
conduct of complicated trials in difficult therapeutic
areas such as cancer. Their experience is in both
treatment and supportive care trials in the cancer
patient.
Email: [email protected]
www.jforcs.com
INTERVIEW: A GLOBAL
CENTRAL LABORATORY
PERSPECTIVE ON ONCOLOGY
STUDIES
1. Let us start with the core competencies of ACM Global Central Lab.
What are your key offerings to the Global Clinical trials Industry?
ACM Global Central Laboratory is a full service reference and Clinical Trial
Central lab. We offer not only a broad menu of assays including safety,
esoteric, microbiology and anatomic pathology and the expertise in our
personnel that perform them but also project management, data
management and study kit building.
2. What are the main requirements from a testing lab? What is being
asked from you now days?
Laboratories are expected to provide results that impact people's lives.
Accurate, repeatable assays implemented after rigorous validation are
required. Molecular diagnostic testing has become a standard request in
protocols. Flow cytometry, PCR and IHC are a routine offering in our
laboratory.
3. How does a testing lab meets high quality standards?
Clinical Trial laboratories are always under the microscope. From formal
regulatory/certifying (CLIA, CAP and NGSP to name a few important to
our clients) agencies to the many client audits requiring adherence to
established industry standards and regional Standard Operating
Procedures (SOP). Participation in various proficiency programs in
conjunction with daily quality control testing demonstrates lab and assay
performance.
4. Whether the method used in the laboratory is sensitive or not?
Validation and initiation of an assay in a lab can depend on the intent of
the evaluation. Validation covers assay, sensitivity, reproducibility, stability
and interference assessments. All must be documented and approved by
the medical director prior to being introduced to the menu of assays
provided by ACM.
5. Is Method having specificity and reproducibility?
It is important that during an assay validation, we accurately determine
the specificity of our assay so as to provide reliable results. Determining
the reportable range is also a key element so as to determine if the assay
meets the clients need for the target population.
6. How do you meet Time deliverable?
Dedicated departments address the specific requirements from request for
proposal and contract to a dedicated laboratory protocol set up team that
work in concert with the project management team to define, validate and
implement study requirements. Due to the level of automation used in our
facilities, and the volume of testing performed on a daily basis, we are able
to maximize the use of our lab. Overall however, our seasoned Project
Managers are responsible for ensuring all key deliverables are met.
34 JCS
7. Do you have have automated testing platform?
Yes we have the Siemens Work Cell with 3 Siemens Advia 1800, 3 Centaurs
with the option to connect the hematology analyzers. All instruments have
back up and are interfaced to the Lab Information System (LIS). This allows
for high throughput making TAT a non issue, scalability for additional large
sample numbers, and reduced specimen volume- always a key concern for
IRB evaluation of new trial approval. The automation allows our scientists
to be utilized in a productive fashion working to implement assays
important to our clients..
8. Do you provide cost-effective solutions?
Yes, ACM Global Central Lab offers a number of cost-effective solutions.
We continually implement state of the art technology, which lowers the
cost to perform testing. For example, we utilize the Siemens WorkCell
robotic line which is interfaced with all our analyzers. Since ACM provides
comprehensive testing such as pathology, microbiology, PGx along with
safety testing, 99% of the testing is performed in one location. When
specimens are parsed out to various labs for testing, there are additional
shipping costs as well as operational costs. Another critical component is
staffing, with a turn over rate of less than 4%, we are able to minimize the
cost associated with hiring and training. As part of a health organization,
we have significant buying power on couriers, collection supplies, etc., which
enables us to pass along additional savings to our clients as well. I
Elena Logan, Vice President, Clinical Trials, US.
Elena's experience is comprised of project management for a
major pharmaceutical company, clinical operations and business
development in the CRO industry and currently as VP, Clinical
Trials for ACM. Email: [email protected]
Kathleen Murray, Executive Director, Global Technical Affairs,
US Kathy has spent over 25 years in the clinical laboratory with
experience in all areas of general laboratory testing. Kathy’s
focus is to expand the ACM’s presence around the globe while
ensuring data harmonisation and standardisation of process.
Email: [email protected]
www.jforcs.com
INTERVIEW:
DATA COLLECTION AND
ANALYSIS FOR THE EARLY
DETECTION OF BREAST
CANCER
1. Let us start with the core offerings of Medidata Solutions. What
are your core objectives?
Medidata Solutions’ mission is to provide hosted clinical development
solutions that enhance the efficiency of customers’ clinical development
processes, and optimise their research and development investments.
We strive to facilitate operational excellence in our customers’ clinical
research processes. We provide software and services designed to
eliminate redundant processes and to increase agility through insightful
decision-making. Our products improve information flow through the study
lifecycle, study design, planning, execution and study close.
Medidata products and services are designed to allow customers to
achieve clinical results more efficiently and effectively by streamlining the
design, planning and management of key aspects of the clinical
development process: protocol development (Medidata Designer™),
investigator benchmarking and budgeting (Medidata Grants Manager™),
contract research organisation (CRO) benchmarking and budgeting
(Medidata CRO Contractor™), and the capture, management, analysis and
reporting of clinical trial data (Medidata Rave®).
Protocol development: Medidata Designer™ is a protocol authoring and
trial design tool that helps guide clinical research teams through the
protocol creation process, also automatically populating downstream trial
applications, such as electronic data collection and data analysis systems
and including clinicaltrials.gov.
Investigator benchmarking and budgeting: Medidata Grants
Manager™, an investigator site contract benchmarking tool, helps trial
managers optimise investigator grants by establishing fair and consistent
site payments and mitigating compliance risks.
CRO benchmarking and budgeting: Medidata’s outsource planning and
contracting solution, Medidata CRO Contractor™, puts data-driven analytic
tools in the hands of research sponsors to efficiently plan, budget and
manage CRO relationships.
Capture, management, analysis and reporting of clinical trial data:
Medidata Rave® is an industry-leading electronic data capture,
management and reporting solution that enhances clinical trial
productivity and provides early visibility to reliable clinical data. Focusing
on user experience and functionality, Medidata Rave provides site
investigators as well as sponsor and CRO study teams with intuitive
interfaces, advanced eLearning tools and accessibility from any
internet-ready computer. Built on industry standards, including CDISC
ODM, and offering a web-based API, Medidata Rave has been seamlessly
integrated with a wide range of clinical trial applications. Recently,
Medidata introduced an extension to Medidata Rave, Rave Monitor. Rave
Monitor offers visit report functionality as an integral part of the EDC/CDM
36 JCS
system, providing sponsors and contract research organisations with a
more efficient, compliant and cost-effective way to manage site visits.
2. How did you get involved with U-Systems? Did you make the initial
contact? What were the project guidelines? Why were you chosen?
U-Systems was looking to replace its paper-based data collection with an
affordable electronic data capture (EDC) system that would increase
efficiencies across its clinical trial process, improve data quality and
maintain a ready audit trail for submission of study data for post-market
approval.
Medidata was chosen for our flexible and affordable implementation
and eLearning capabilities. Additionally, U-Systems was attracted to our
focus on small to mid-sized companies and its ability to deliver fast
implementations while collaborating with our sponsors and addressing
their needs.
With Medidata’s help, U-Systems was able to launch it’s first-ever EDC
trial in just six weeks. Medidata Rave’s built-in eLearning functionality was
critical for U-Systems to quickly train site staff to become proficient in Rave,
saving both time and cost in study start-up. Medidata’s eLearning tool also
enabled U-Systems to easily certify that all study coordinators completed
training before entering study data, as access to the study is blocked until
successful completion of the training – a key enabler of audit trail
documentation. With the potential for this initial study to grow to nine
sites, U-Systems expects to continue to rely on Medidata Rave’s ability to
quickly train site personnel in order to achieve timely and accurate data
entry and review.
3. Coming to the operational procedures, is there any facility to check
for out of range values when data validation happens automatically
when data is entered in to the eCRF online?
One of the prime benefits of Medidata Rave is its automatic flagging of
“out of range” values as soon as a site enters in the eCRF. Rave can handle
both local and centralised laboratory limits, and also check for multiple
data dependencies. For example, this can allow for range checking based
on age or physiological status (e.g. fasting) or using multiple analytic unit
conversions. In addition, the edit check engine can reference both data
entered through eCRFs or loaded data such as lab, serologic or
pharmacokinetic data.
4. Is there automatic reminder for a subject’s next visit?
Medidata Rave’s built-in tools can provide a clear visual cue to the end user
to alert them to the need to follow up on overdue visit data. In addition,
Medidata Rave features an edit check triggered messaging functionality
www.jforcs.com
of the clinical development process. Below are some examples of features
that are particularly useful in oncology trials.
Nesting of folders/events within a study outline
This feature supports concepts like treatment cycles within time periods.
This facilitates downstream processing such as edit check and reporting
comparisons.
Dynamic fields, forms, visit schedules
Fields, forms, and cycles can be added manually or based on an event or
trigger. For example, a schedule can be added for a new course of
treatment if the previous treatment failed or a new cycle can be
dynamically created based on a lab result for white blood cell count.
Imaging support
Medidata Rave supports the ability to upload different types of images so
that they can be viewed and compared on a visit by visit basis alongside
things such as tumour measurement data.
which can be used to send predefined alerts to end users concerning
upcoming events such as visits.
Medidata Rave can also be interfaced with systems from organisations
that provide mobile-based medical alerts to patients to remind them of
upcoming visits.
5. Will the system provide automated support for generating
invoices when certain milestones are met for each subject?
Medidata Rave can be integrated with other systems to trigger messages
or activities based on study events or milestones. For example, Medidata
Rave has been integrated with financial and CTMS systems to produce
invoices based on the achievement of specific milestones and events within
a study. Medidata Rave does not produce such invoices from within the
system.
6. Will the system ensure agency-specific document formatting and
publishing?
Medidata Rave provides a sponsor with submission-ready PDFs, formatted
in accordance with agency-defined formatting specifications for electronic
submission of clinical study data. In addition, the PDF outputs include full
audit information which can be used for the site and sponsor archival of
the study data.
7. Will the system perform as liaison between regulatory bodies and
the sponsor company?
Medidata is available as a resource for guidance on local, national and
international regulatory requirements, when working with sponsor and
CRO organisations. Medidata does not get directly involved with
inspections by a regulatory authority; however, when sponsors are being
inspected, Medidata makes itself readily available to support the sponsor
and to help them respond to regulatory questions and requests.
8. What is Medidata's next big project? Any more innovative data
collection and analysis tools on the oncology front?
Medidata continues to develop new ways to help our clients fulfill their
clinical research objectives. We provide robust tools which enable our
oncology customers to conduct faster, more efficient trials. Approximately
34% of the studies currently conducted in Rave are in the oncology
therapeutic class. Rave is highly configurable and we continuously seek to
add functionalities to streamline the design, planning and management
38 JCS
Sophisticated lab system
Medidata Rave has robust capabilities in both central and local labs. This
allows the ability to monitor lab data alongside hand-entered data,
including tracking against reference and alert ranges. Ranges are time
sensitive and can utilise any data points in the study. The central lab upload
tool has to the ability to ensure data is matched to the proper patient and
visit, and if it is a new or incremental update.
Sophisticated security engine
Medidata Rave utilises a single security engine for all inputs, outputs and
reporting. This also allows for sophisticated blinding and unblinding of
efficacy data by study phase and can be very useful in adaptive trials.
Configurable patient statuses
Beside the statuses of enrolled, screening, and failed, any other status can
be created. Examples may be “completed cycle 1, completed cycle 2.” This
facilitates outputs and reporting.
“Snowbird” support
Within Rave, we have the ability to transfer or share patient records
between clinics and sites. This is very useful in areas such as patient
relocation i.e. to warmer climates for the winter or when an investigator
moves from one institution to another and the patients follow. Included
in this support is a complete audit trail of all movements and activities.
Global Library and Architect Loader
These utilities provide the ability to rapidly deploy studies based on
standards. They also provide the ability to easily share study designs across
related areas.
All our customers, including some of the largest players in the field of
oncology, play a key part in the ongoing development of Medidata Rave.
This has enabled us to take into account key data collection and analysis
needs in the field of oncology. I
Steve Heath, VP and Head of EMEA. Steve is
responsible at Medidata for commercial and operational
activities within EMEA. Steve has wide familiarity of
selling and implementing EDC (electronic data capture),
CDM (clinical data management) and ePRO (electronic
patient reported outcomes) systems as well as LIMS,
clinical project management, safety and adverse drug
reaction reporting systems.
David Quarm, Senior Business Consultant, Medidata
Solutions
www.jforcs.com
QTC PROLONGATION IN
PATIENTS WITH CHRONIC
RENAL IMPAIRMENT
Introduction
Patients with end-stage renal disease are frequently associated with
increased mortality rates due to sudden cardiac events (1-8). Ventricular
arrhythmias are the major problems of cardiac origin (9) in this population.
Several attempts have been made to determine factors responsible for the
occurrence of serious ventricular arrhythmias (7, 10, 11). It was shown in
previous clinical studies that prolongation of QT interval and changes in
the QT dispersion on the surface electrocardiogram may correlate with the
onset of serious cardiac arrhythmias (12, 13). This investigation was
performed to elucidate a possible correlation between the status of renal
impairment and QTc prolongation in patients with different stages of renal
impairment and healthy controls.
Material and Methods
Screening data of 43 patients with different stages of renal impairment
and 28 healthy subjects from three clinical studies were analysed. Table 1
summarises the demographic data. All studies were approved by the
central ethics committee in Chisinau, Moldova and the studies were
performed in the clinical site of INNOPHAR at the National Institute of
Cardiology. Renal impairment was documented by creatinine clearance
(CLCR) calculated according to the formula of Cockcroft-Gault. Patients
with clinically relevant cardiac diseases were excluded. Patients with
controlled hypertension were only included if they did not take any
medication which might have an effect on QT interval.
Table 1: Demographic Data
H
RI
H
RI
H
Results
Table 1 shows that the demographic data of both groups were comparable.
In particular, heart rate (HR) was not significantly different in both groups
(p = 0.679). Also the gender distribution was comparable in both groups
(57% and 58% females, and 43% and 42% males in the group of
healthy and renal impaired patients respectively). There was a statistically
significant difference in the CLCR between the healthy controls and the
renal impaired patients (p << 0.001). Figure 1 presents the arithmetic
mean values for CLCR.
Figure 1: Mean CLCR (mg/ml)
(H=healthy, RI=renal impaired)
H
43
28
43
28
43
Minimum
23,00
22,00
52,00
46,00
54,00
49,00
Maximum
64,00
68,00
100,00
92,50
90,00
91,00
Median
48,00
47,00
72,70
70,00
66,50
67,00
Mean
47,07
46,19
73,75
69,47
68,50
67,51
SD
10,25
11,99
12,24
12,33
9,05
10,80
There was also a statistically significant difference in the arithmetic mean
of QTc (p << 0.001) between healthy controls and patients with renal
impairment (refer to Fig 2).
Figure 2: Mean QTc in ms
(H=healthy, RI=renal impaired)
H
After a comprehensive physical and laboratory investigation, rest ECGs
with 12 lead standard deviations were recorded according to the standards
published previously (14). QT was calculated as the mean value from
10-second ECG recordings as the difference from beginning of the Q-wave
and the end of the T-wave by using the Dr. Vetter PC-ECG (Dr. Vetter
GmbH, Germany). All subjects were investigated in a supine position in the
fasting state after a resting period of at least 15 minutes. The room for
ECG recordings was noise-protected and the temperature was kept
constant at 22±2°C. QT was corrected according to the Bazet Formula
QTc = QT*(60/HR)-1/2. As the last phase of the repolarisation process is
potassium-dependent serum potassium was also investigated. CLCR data
were log-transformed because there is a bottom effect like in other
laboratory data, and the data are left skewed and therefore deviate from
normal distribution. All metric data were analysed by t-test, and categorical
data were submitted to a Pearson-Chi-Square-Test. The critical statistical
40 JCS
RI
RI
28
N
level was defined as 5% in general. A regression analysis with a linear
model (ANCOVA) was performed to investigate whether age, weight and
gender have an influence on the correlation of CLCR and QTc.
RI
The scatter plot in Figure 3 confirms the correlation between CLCR (on
log-transformed axis) and QTc.
Figure 3: QTc (ms) vs
CLCR (in log-scale)
www.jforcs.com
The regression analysis reveals a statistically significant correlation
between CLCR and QTc (p < 0.001). The ANCOVA analysis confirmed that
there was no statistically significant influence of age and weight on the
correlation between CLCR and QTc (p > 0.05). A statistically significant
difference (p = 0.05) in QTc was observed between males and females
(428,20 ms for males and 442,94 ms for females).
Figure 4: QTc (ms) in Females
and Males
F
M
There was also a statistically significant difference in serum potassium
between healthy subjects and renal impaired patients (refer to Table 2).
Table 1: Serum Potassium (mmol/l)
Healthy
28
4.262
0.558
Renal Impaired
41
4.878
0.751
<0.001
The scatter plot in Figure 5 reveals that the slope in the correlation between
heart rate and QT is different in healthy subjects and in renal impaired
patients.
Figure 5: Correlation heart rate (HR;
b/min) vs QT-Interval (QT; ms)
Discussion
This investigation was performed to analyse the possible correlation
between renal impairment based on CLCR and QTc prolongation in
patients with different degrees of renal impairment in comparison to
healthy subjects. The data revealed a statistically significant correlation
between CLCR and QTc corrected according to Bazet. This result is
consistent with previous investigations (15) in which significant QTc
prolongation was described in chronic renal impaired patients who had
recently started hemodialysis. The mechanisms responsible for QTc
prolongation in patients with chronic renal impairment are not completely
understood. There are controversial results published. The investigation of
Voiculescu et al. (16) revealed that QTc prolongation was not correlated
with the stage of renal impairment but with the duration of renal
impairment. There were speculations on the influence of autonomic
neuropathy (17, 18) on the development of QTc prolongation because it
was found not only in patients with renal impairment but also in patients
with diabetes mellitus (19-24) or hepatic impairment (25-28), which seems
to confirm that QTc prolongation is triggered by autonomic neuropathy of
different origin. Reports on hepatic impaired patients who underwent liver
transplantation reveal that QTc normalises in most cases within one month
(29, 30) whereas autonomic neuropathy is not reversible in all
patients (29). Autonomic neuropathy if present may contribute to the QTc
prolongation but there must be other factors which are more important.
As can be seen from the scatter plot (refer to Figure 5) the slope is different
42 JCS
between healthy subjects and renal impaired patients.
This may be an indicator that the correlation between HR and QT is
changed by renal impairment. Electrolyte imbalance which is commonly
present in renal impairred patients may have an impact on the
electrophysiological correlation between HR and QT. A significant
difference in serum potassium observed in the investigated population
confirms this hypothesis, but further investigations will be necessary to
come to a final conclusion. The differences in QTc for gender were already
described in a previous investigation (31) and may be taken as
confirmation that the present investigations were performed to a good
quality standard. I
References:
1. Morris KP, Skinner JR, Wren C, Huner S, Coulthard MG. Cardiac abnormalities in end stage renal failure
and anaemia. Arch Dis Child 1993; 68: 637 – 643.
2. Shpira OM, Bar-Khayim Y. ECG changes and cardiac arrhythmias in chronic renal failure patients on
hemodialysis. J Electrocardiol 1992; 25: 273 – 279.
3. Thomson BJ, McAreavery D, Neilson JM, Winney RJ, Ewing DJ. Heart rate variability and cardiac
arrhythmias in patients with chronic renal failure.
4. Ramirez G, Brueggemeyer CD, Newton JL. Cardiac arrhythmias on hemodyalisis in chronic renal failure
patients. Nephron 1984; 36: 212 – 218.
5. Weber H, Schwarzer C, Stummvoll KH et al. Chronic hemodialysis: high risk patients for arrhythmias?
Nephron 1984; 37: 180 – 185.
6. Singh JP, Sleight P, Kardos A, Hart G. QT interval dynamics and heart rate variability preceding a case of
cardiac arrest. Heart 1997; 77: 375 – 377.
7. Nakamura N et al. QTc dispersion in haemodialysis patients with cardiac complications. Nephrology
2005; 10: 113 – 118.
8. Raizada V et al. Renin-angiotensin polymorphsisms and QTc interval prolongation in end-stage renal
disease. Kidney International 2005; 68: 1186 – 1189.
9. Kocak G et al. QT/corrected QT (QTc) intervals and QT/QTc dispersions in children with chronic renal
failure. International Journal of Cardiology 1999; 70: 63 – 67.
10. Ichikawa H, Nagake Y, Makino H. Signal averaged electrocardiography (SAECG) in patients on
hemodialysis. J Med 1997; 28: 229 – 243.
11. Goldner B, Brandspeigel HZ, Horwitz L, Jadonath R, Cohen TJ. Utility of QT dispersion combined with the
signal-averaged electro-cardiogram in detecting patients susceptible to ventricular tachyarrhythmia. Am J
Caridol 1995; 76: 1192 – 1194.
12. Kirvela M, Yli-Hankala A, Lindgren L. QT dispersion and autonomic function in diabetic and non-diabetic
patients with renal failure. Br J Anaseth 1994; 73: 801 – 804.
13. Örincz I, Zilahi Z, Kun C, Natyus J, Kakuk G. ECG abnormalities in hemodialysis. Am Heart J 1997; 134:
1138 – 1140.
14. Eckl KM, Sydorchuk L, Biletski S, Tsvitbaum N, Wadepuhl T, Thomsen T, Darius H. The reliability of QTc
interval assessment. AGAH annual meeting, 23-25 February, Bonn, Germany.
15. Beaubien ER, Pylypchuk GB et al. Value of Corrected QT interval dispersion in identifying patients
initiating dialysis at increased risk of total and cardiovascular mortality. Am J of Kidney Diseases 2002,
39(4): 834.
16. Voiculescu M, Ionescu C, Ismail G. Frequency and prognostic significance of QT prolongation in chronic
renal failure patients. Rom J Inern Med 2006, 44(4): 407 – 417.
17. Kirvela M, Yli-Hankala A, Lindgren L. QT dispersion and autonomic function in diabetic and non-diabetic
patients with renal failure. Br J Anaesth 1994, 73: 1814.
18. Kurosu M, Ando Y et al. Factors related to the QT prolongation in chronic renal failure. Nippon Jinzo
Gakkai Seri 1999, 41(2): 70.
19. Brown DW et al. Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are
associated with prolonged QTc duration. Results from the third national health and nutrition examination
survey. J Cariovasc Risk 2001, 8(4): 227 – 233.
20. Sawicki PT, Dahne R, Bender R, Berger M. Prolonged QT interval as a predictor of mortality in diabetic
nephropathy. Diabetologica 1996; 39: 77 – 81.
21. Ewing DJ, Boland O, Nielson JM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval lengthening,
and unexpected deaths in male diabetic patients. Diabetologica 1991; 34: 182 – 185.
22. Kahn JK, Sisson JC, Vinik AI. QT interval prolongation and sudden death in diabetic autonomic
neuropathy. J Clin Endocrinol Metab 1987, 64: 751 – 754.
23. Belavere F, Ferri M, Guarini L, Bax G, Piccoli A, Cardone C, Fedele D. Prolonged QT period in diabetic
autonomic neuropathy: a possible role in sudden cardiac death? Br Heart J 1988; 59: 379 – 383.
24. Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; I:
14 – 16.
25. Thuluvanth PJ, Triger DR. Autonomic neuropathy and chronic liver disease. Q J Med 1989; 72: 737 –
747.
26. Hendrickse MT, Triger DR. Peripheral and cardiovascular autonomic impairment in chronic liver disease;
Prevalence and relation to hepatic function. J Hepatol 1992; 16: 177 – 183.
27. MacGilchrist AJ, Reid JL. Impairment of autonomic reflexes in cirrhosis. Am J Gasroenterol 1990; 85:
288 – 292.
28. Oliver MI, Mirales R, Rubies-Prat J, Navarro X, Espadaler JM, Sola R, Andreu M. Autonomic dysfunction in
patients with non-alcoholic chronic liver disease. J Hepatol 1997; 26: 1242 – 1248.
29. Mohamed R, Forsey PR, Davies MK, Neuberger JM. Effect of liver transplantation on QT interval prolongation and autonomic dysfunction in end stage liver disease.
30. Finucci G, Lunardi F, Sagerdoti D, Volpin R, Bortoluzzi A, Bombonato G, Angelli P, Gatta A. QT interval
prolongation in liver cirrhosis. Reversibility after orthotopic liver transplantation. Jpn. Heart J 1998, 39 No 3:
321 – 329.
31. Moss AJ. The QT interval and torsade de pointes. Drug Safety 1999, 21(1): 5 – 10.
Contributed By: Cornea N., Wadepuhl M., Tsvitbaum N.,Janik F., Eckl K.M.
Natalia Cornea worked as a Nephrologist in the Dialysis and
Kidney Transplantation Center of Clinical Republican Hospital.
During these years she also participated in many scientific
conferences, courses and symposia in Moldova, Romania,
Hungary, Ukraine and Poland. Natalia took an active part in
carrying out the “IV Congress of Urology, Hemodialysis,
Transplantology with international participation” Chisinau,
Moldova being on the scientific and organizational board.
Email: [email protected]
www.jforcs.com
DIGITAL PEN AND PAPER
HELP UN BODY
FIGHT DISEASE IN AFRICA
The United Nations Food and Agriculture Organization (FAO), is
using Digital Pen and Paper technology to virtually eliminate the
need for ‘traditional’ data entry, enabling near-instant field reports
to prevent or limit the effects of infectious diseases, drought and
flooding in sub-Saharan Africa.
Since its foundation in 1945, the UN’s FAO has focused special
attention on developing rural areas – home to 70 per cent of the world’s
poor and hungry people. Its role is to lead international efforts to defeat
hunger, and it serves as a knowledge network to help developing and
transitional countries modernise and improve agriculture, forestry and
fishery practice, to ensure good nutrition for all.
Most of the FAO’s missions are in remote regions with little or no access
to electricity, computer facilities or telecommunications infrastructure. This
severely restricted the availability of timely information from the various
collecting sources to enable appropriate decision-making and efficient,
well-timed action.
Hand-written information gathered by local veterinary assistants and
FAO staff in the field could end up being stored for weeks or months before
it reached District Veterinary Offices and FAO analysts based in Rome, Italy.
The result was frustration at all levels. By the time FAO headquarters had
made their analyses, a disease outbreak may already have wiped out
livestock for example. In rural sub-Saharan Africa, such events are
particularly devastating, as a big part of the population – as much as
two-thirds of the population – depends on livestock for its living.
The importance of livestock health
Livestock is an important sector of agricultural production in the countries
of the Southern African Development Community (SADC), accounting for
20 to 40 per cent of the agricultural gross domestic product, and holds a
high social value for rural communities in the region.
Moreover, there is ever-increasing demand for livestock and livestock
products in the region. Estimates by the SADC indicate that over the next
10–15 years, the average annual consumption of meat and milk will more
than double from 7kg to 15kg of meat and from 20 to 50 litres of milk per
person in the region.
Ambitious export strategies have been developed to alleviate poverty
in sub-Saharan Africa. However, severe drought since 2000 has limited
grazing and water points.
A chronic shortage of resources, land disputes and a crippling HIV/AIDS
epidemic has severely limited communities’ ability to cope with outbreaks
of trans-boundary animal diseases (TADs), which are the most important
barrier to market access for livestock and livestock products.
Outbreaks of TADs in previously disease-free areas of SADC countries
over the past few years have endangered the animal health status of the
entire region and threatened the livelihoods of more than half of the
population.
Outbreaks of disease can result in massive animal and economic losses.
For example, an outbreak of Foot and Mouth Disease (FMD) in 2001 led
to the suspension of beef exports from Zimbabwe to European countries.
In Botswana, thousands of cattle had to be slaughtered following an
44 JCS
outbreak of Contagious Bovine Pleuropneumonia (CBPP) in 1995, and
subsequent control of the disease and restocking has been a costly exercise
for the government.
This is why the FAO places such emphasis on its programme to
eliminate or alleviate the damaging effects of disease, and sudden drought
or flood.
In 2004, the FAO began a project in to implement emergency control
of epidemic FMD, CBPP and other dangerous animal diseases, such as
Anthrax, in southern Africa.
An ‘almost revolutionary’ solution
To help streamline the work of the FAO, South African IT company Xcallibre
developed a new real-time data collection application based on Anoto’s
digital pen and paper technology. This works in combination with mobile
handsets and networks – increasingly widely available in Africa – to get
field data to the people who need it fast.
Field agents can register data with the digital pen on to a special form.
The information is saved in the pen’s memory, before it is transmitted via
a mobile or fixed internet connection. Next, the data is processed and sent
by e-mail to the appropriate people at the local District Veterinary Office
or FAO headquarters – who can then return instructions to field staff on
what steps to take.
This digital pen and paper application is now being used by regional
and national authorities in Namibia, Zambia, Mozambique, Malawi,
Tanzania and Zimbabwe.
”The pen is an almost revolutionary way to overcome a big problem
with gathering data from the field and making timely decisions in case
quarantine needed to be imposed,” says Fred Musisi, the FAO’s Regional
Emergency Livestock Officer. “If there is a case of rabies or an outbreak of
a deadly disease, a field worker can send the detailed surveillance data
immediately only using a mobile phone. In the worst case, if there is no
mobile network nearby, the field worker simply moves to a location with
mobile coverage or finds the nearest fixed internet connection. But no
longer do they have to drive hours back to a capital city before the
information can be confirmed.”
Simplicity and speed
Other mobile-based computers (such as PDAs) were initially considered as
an alternative information tool, but this idea was discarded for a number
of reasons: the need for batteries, the length of the questionnaires and a
legal requirement for signatures on the forms.
The adoption of the digital pen and paper as a data capture tool was
relatively easy, and overcame the challenges of PDA-type solutions.
Xcallibre and Anoto developed a non-technical ‘train the trainer’ approach
for the roll-out. FAO country representatives now implement the solution
on their own as more users come on board. Ease of use was a key
consideration in the design of the forms.
With the help of digital pen and paper, information transfer is
accelerated and all relevant users and offices can simultaneously receive
secure and controlled access to the information collected. The solution has
www.jforcs.com
also improved the information management capacity, since the data
collection methods can now be standardised throughout the sub-region.
The ability to gather and analyse data in virtually real time leads to
significant benefits for the FAO’s monitoring and early warning systems.
These include improvements in disease surveillance and information flow,
both at national and regional levels; the establishment of active
surveillance programmes to monitor situations in different ecosystems;
and impact assessment and risk analysis as part of the effective control of
TADs.
Wider benefits
Overall, the FAO has greatly improved the collection, processing and
distribution of information on TADs across the participating countries. It
has reduced the time it takes to get a form to regional or national offices
for capture down from one to three months to a matter of minutes in areas
with mobile phone coverage.
With this near real-time data, the FAO is able to represent outbreak
patterns spatially and use spatial analytic techniques to develop response
mechanisms. A web-based editing and reporting tool gives all users and
offices simultaneous, secure and controlled access to the information
collected.
The main beneficiaries of FAO’s TAD control projects are the owners
and keepers of 2.14 million head of cattle in target areas in Malawi, the
Caprivi Region of Namibia, Tanzania, Zambia and Zimbabwe. The spread
of dangerous livestock diseases within and across international borders
has been successfully contained in all five countries. No new cases of FMD
have been reported in intervention areas in Malawi. No new cases of
Anthrax have been reported in the Caprivi Region of Namibia since January
2005, and reporting of new cases of CBPP has continued to decline
substantially in southwest Tanzania.
The FAO helped successfully control the CBPP epidemic in Zambia and
contributed to completion of the first phase of progressive elimination of
FMD in Zimbabwe. In addition, the FAO helped Zimbabwe to reclaim part
of the beef export zone, as well as minimise losses in national milk
production.
The FAO is now considering using the application as standard
procedure in its field missions in Asia and Latin America as well. In addition
to this, they are also considering new areas of application, for example as
a tool to combat HIV/AIDS.
For the Xcallibre and Anoto team, the next challenges are to find
alternative transmission methods – such as satellite phones – where mobile
cellular coverage or fixed internet access is poor or unavailable. Other
possible developments include the use of solar chargers for charging digital
pens, mobile phones, laptops and satellite phones. The team is also
considering the use of Bluetooth® GPS devices to capture the pen’s
location for browser-based mapping and analysis.
Thanks to the efforts of the FAO, and their creative use of Digital Pen
and Paper technology, the people of sub-Saharan Africa can look forward
to a more secure and prosperous future.
How DPP technology works
Digital Pen and Paper technology works by remembering what has been
written or drawn on special, dotted paper, and transmits this data back to
a PC or server. The digital pen writes just like a normal ballpoint pen, but
has a tiny infrared camera at its tip, which reads and records the
movements of the pen relative to a pattern of grey dots printed on normal
paper. The dot pattern can be generated using a standard printer.
For mobile staff, digital pen and paper allows them to fill in forms on
the move without the need to return to the office and type them up later
in the day. Users can either send the data back to the office via Bluetooth
and a mobile phone – or wait until they return to their desk to dock the
pen and instantly transfer the information.
46 JCS
The FAO’s field agents register data with an Anoto Digital Pen into a
customized form, then the informa¬tion is saved in the pen’s memory,
awaiting transmission using GPRS or internet. Next, the data is processed
and sent by e-mail to the relevant actors (District Veterinary Office, FAO
headquarters), which can return instructions to field staff on what steps to
take.
Figure 1: Digital Pen and Paper
Technology (DPP)
Partner Profile: Xcallibre
The South African company Xcallibre is a new-age global technology
services company, which sets out to deliver end-to-end business solutions
to its clients. It comprises highly-skilled people and a network of strategic
partners, all specialists in their respective fields. Xcallibre brings together a
unique combination of mobility technologies and highly advanced service
infrastructure, to create a forms/document processing solution with the
ability to transfer handwritten and/or digital notes and forms to your
back-office, as graphical images and fully loadable data files. Xcallibre
delivers a wide portfolio of innova¬tive business process systems to its
clients in a number of sectors, including insurance & banking and
healthcare.
Customer Profile: The Food and Agriculture Organization (FAO)
The FAO is a United Nations organization that leads international efforts
to defeat hunger. FAO also helps developing countries and countries in
transition to modernise and improve agriculture, forestry and fishery
practices and to ensure good nutrition for all. Since its foundation in 1945,
FAO has focused special attention on developing rural areas. I
Urban Froderberg. After his education at Uppsala
University, Sweden, Urban Froderberg started his
career in the pharmaceutical business at German
Boehringer Ingelheim. He joined Swedish Astra in
1988 where he held several successful positions
within Marketing & Sales. He has worked with
business development etc. at AstraZeneca, in all a
twenty years experience within the pharmaceutical
business. Since August 2007 Froderberg serves as
Business Area Manager, Healthcare, at Swedish
Anoto AB the company, leading in the unique
technology for digital pen and paper. Email: [email protected]
www.jforcs.com
JOURNAL FOR
U
CLINICAL STUDIES
Your Resource for Multisite Studies & Emerging Markets
London, UK, April 16, 2009: Chiltern International
Limited (Chiltern), a global Clinical Research
Organization (CRO) providing clinical development
and staffing services in Europe, the Americas and
India, today announced the acquisition of Vigiun,
a full service Clinical Research Organization located
in São Paulo, Brazil.
Established in 1999 by Eduardo Forleo, MD, and
Elisa Halker, BSN, Vigiun has extensive experience
conducting clinical trials in a variety of therapeutic
areas, in particular infectious disease, oncology, and
respiratory.
“We warmly welcome Vigiun to the Chiltern team,”
stated John Vann, Executive Vice President,
Americas. “The acquisition of Vigiun enhances
Chiltern’s growing presence in Latin America, which
was established nearly a year ago when we began
operations in Argentina under the leadership of
Oscar Podestá, our General Manager for Latin
News
America. The knowledge and experience of
Eduardo Forleo and Elisa Halker, and all of the
Vigiun staff, will further strengthen our ability to
serve our clients and continue our strategy for
growth in the region.”
Dr. Forleo has been appointed Chiltern’s Country
Manager for Brazil and Medical Director for Latin
America. Ms.Halker will serve as Director of Clinical
Operations for Brazil.
Said Dr. Forleo, “This is an exciting time to become
a part of Chiltern. Our business has grown to the
point that it makes sense to join forces with a global
CRO whose mission and values align with ours. I
look forward to contributing in very positive ways to
the company’s ongoing and future success.”
“I am very pleased to have Vigiun join Chiltern,” said
Glenn Kerkhof, Chiltern’s CEO. “Vigiun is an ideal
complement to our existing Latin American
operations and Chiltern’s presence in 27 other
countries as we serve the pharmaceutical and
biotech industries globally.”
Latin America has a population of 503 million
people, of which 192 million are in Brazil. This vast
population provides a significant number of
potential patients in all disease areas. Latin America
is rich with experienced investigators and is known
for high quality data and excellent patient retention
in clinical trials.
For More Information Contact:
Mac McElroy Stuart McGuire
Chiltern International Inc. Chiltern International Ltd.
1241 Volunteer Parkway 171 Bath Road
Suite 950 Slough
Bristol, TN 37620 Berkshire SL1 4AA
USA UNITED KINGDOM
Tel: +44 (0) 1753 512 000
Fax: +44 (0) 1753 511 116
Email: [email protected]
AUSTRALASIA
Your Stepping Stone to Market
JOURNAL FOR
U
CLINICAL STUDIES
Your Resource for Multisite Studies & Emerging Markets
Compiled by
Contents
Overview of Australasia Early Phase Clinical Trial Environment
54
Australia and New Zealand offer medicinal product developers much more than just an efficient regulatory
framework. Of paramount importance to those planning clinical trials are the availability, suitability and interest
of clinical researchers together with volunteer populations, whether that be healthy people or patients with the
indication being researched, that are motivated and accessible within ever decreasing timelines. Russell Neal of
Clinical Network Services (CNS) explains why Australia and New Zealand offer an increasingly attractive “one-stop
shop”, in terms of time, delivery and cost, in early phase research.
Conducting Early Phase Clinical Trials in Australia.
56
Phase I clinical trials are a critical stepping stone in product development pipelines for biotechnology and
pharmaceutical industries. These trials are crucial because they are used to establish the safety and tolerability of
new products in humans and thereby determine if they are safe to proceed into further clinical testing. Nathan
Martinez, Executive Officer of Q-Pharm, shows how Australia offers an attractive proposition for conducting early
phase clinical trials from quality, efficiency and economic perspectives.
Australia says G’day to Clinical Trials!
60
Australia offers a number of significant advantages as a site for clinical trials one of which is a clear, affordable
and uncomplicated regulatory environment. There is a straightforward and rapid regulatory process for the
approval of clinical studies for most investigational medicinal products, including biologics in some cases. Dianne
Jackson-Matthews, Director of ERA Consulting’s Australian office outlines the regulatory pathways for clinical trials
in Australia.
Australian Bioanalytical Expertise for Preclinical and Clinical Studies
63
Australia has a rich history of success in the drug development and clinical trial industries. An essential part of that
process is the provision of quality bioanalytical services to meet the needs of both the preclinical and clinical stages
of development. Russell Addison of TetraQ analyses Australia’s significant capabilities and expertise in providing
bioanalytical services for preclinical and clinical studies for the international pharmaceutical and biotechnology
industries.
Translational Research – the Bioinformatics Challenge
66
The discovery and development of effective new and modern therapies can be achieved using a translational
research approach. Translational research draws on the expertise of the biological researcher, clinician,
biostatistician and computer scientist to discover the basis of disease and to translate that knowledge into
therapies. Jeremy Barker and Dominique Gorse of QFAB highlight the following case studies: KOALA Childhood
Obesity Program, Nuclear Receptors in Breast Cancer, Australian Prostate Cancer Research Centre, Innovative
Wound Management.
Queensland Biotechnology – Ripe for the Picking
70
There are many regions around the world jockeying to become local biotechnology powerhouses. Few, however,
possess Queensland’s unique environment for biotechnology growth according to Professor Peter Andrews,
Queensland Chief Scientist.
Enabling a Networked and Collaborative R&D Environment
73
Biopharmaceutical companies are looking at new R&D business models by compartmentalising, outsourcing and
networking their R&D activities with a multitude of research organisations. Given the explosive development in
the application of high-end computing, laboratory automation and molecular science, QCTN has pulled together
a cluster of Australian R&D service providers with excellent and mutually complementary capabilities in the fields
of translational and clinical research, supported by a robust bioinformatics and biostatistics infrastructure. Otto
Damsma of QCTN explains QCTN’s role in coordinating and facilitating national and international sponsors and
its members - Australian R&D service providers.
Facilitating Genomics and Translational Research
77
As a result of the mapping of the human genome, along with recent significant advances in technologies used to
study genomes, genomic research is now yielding increased amounts of information and understanding about
the role and function of genes in human disease. Tony Feneziani of Australian Genome Research Facility Ltd
explains the role of AGRF in supporting translational research.
www.jforcs.com
JCS 51
Editor’s Note
Australasia: a Stepping Stone to Markets
Australasia is frequently used as a term to describe the region of the world that encompasses Australia and New
Zealand together with the many Asian nations immediately to our North. In this special supplement, researchers
and managers active in several organisations from Queensland, Australia, provide an insight into the clinical and
translational research capabilities in Australia and New Zealand, with an emphasis on the former. Queensland
is known in Australia as the ‘Smart State’ and it is experiencing the most sustained period of growth and
prosperity ever recorded in the State’s history.
While Queensland continues to grow, in spite of the global economic downturn, it has established a
position with the best in the world in pharmaceutical and biotechnology research and development and is fast
becoming an important international hub for translational medical research and the biotechnology industry. In
his article “Queensland Biotechnology – Ripe for the Picking”, Prof. Peter Andrews, Queensland Chief Scientist,
provides a bird’s eye view of more than a decade of strong and focused investment by the Queensland
Government in both academic and industrial players in the fields of life sciences, biotechnology, tropical sciences
and other sectors.
Mario Pennisi
Chief Executive Officer
Queensland Clinical Trials Network Inc.
(QCTN)
Attractive landscape
Australia is renowned for its beautiful and unique flora, fauna, landscape and shores. In his overview article,
Russell Neal of CNS Pty Ltd describes the clinical trial landscape in Australia and New Zealand, the rise of
specialised early phase clinical research units and practical aspects and considerations for undertaking clinical
research in Australia. The reasons why one would choose Australia for early phase clinical trials, and the
advantages of Australia’s regulatory system, are further highlighted in the article by Nathan Martinez of
Q-Pharm Pty Ltd, a phase I/II unit based in Brisbane, as well as by Dianne Jackson-Matthews of ERA Consulting
(Australia) Pty Ltd. In her informative article, Dianne Jackson-Matthews provides case-studies concerning the
regulatory pathways for clinical trials involving biologicals, cell therapy and small molecules.
No preclinical or clinical studies can be performed without bioanalysis of samples and ADME analysis. TetraQ
is a provider of bioanalytical services, as well as offering efficacy investigations using disease models (pain,
Alzheimer’s and others), toxicology and pharmaceutics services. TetraQ is accredited by Australia’s National
Association of Testing Authorities in the field of R&D and is compliant with the OECD principles of Good
Laboratory Practice.
Refreshing
The clinical playing field will be familiar to many readers, but the way clinical research is undertaken in Australasia
and the breadth and depth of opportunities that exist in the fields of translational medical research and
bioinformatics will be both remarkable and refreshing. Remarkable in terms of the technical resources and
expertise available in Australasia to conduct genomics and other “omics” research, and refreshing in the way a
coordinated network of industrial and academic R&D service providers can be identified and accessed through
the facilitation of an independent industry group QCTN.
QCTN is to a large degree the result of the foresight of the academic and industrial life sciences community
with the strong support of the Queensland Government. They realised that a coordinated response was necessary
to assist the biopharmaceutical industry in its search for new R&D business models in order to increase their
productivity and efficiency in product development, and established QCTN in 2005. As explained in the article
by Otto Damsma, at QCTN, outsourcing R&D activities is one of the solutions that biopharmaceutical companies
need to explore, but the way in which this is aligned with the R&D strategies and the way it is set up and managed
are success-determining factors that need new consideration in the era of internet, high-throughput screening,
bioinformatics and genetic profiling. Jeremy Barker, CEO, and Dominique Gorse, Technical Manager, of the
Queensland Facility for Advanced Bioinformatics, and Tony Feneziani, Manager at the Australian Genome
Research Facility Ltd, whose contributions can be found in this journal, represent just two of the many research
institutes active in the translational field.
Capacity for more
While Queensland-based organisations are highlighted in this issue, the reader should consider these
organisations to be representative of the preclinical, clinical and translational research facilities and capabilities
available in Australia and New Zealand. Both countries have modern Western societies and healthcare
environments. Nonetheless, the cost of R&D is still relatively low compared to other Western countries and Japan.
Information provided by respected market analysis companies suggest that there is a potential for doubling
the value of R&D work undertaken in Australia. The extra capacity for both translational and clinical research in
Australasia represents a wonderful opportunity for Asian and Western biopharmaceutical and medical device
companies to access quality researchers and reduce time-to-market, and will be on show later this year at the
TRX09 symposium in Brisbane. Australasia can serve as a stepping stone to these markets, since data generated
in preclinical and clinical studies in Australia and New Zealand are generally well received by the American and
European regulators.
52 JCS
www.jforcs.com
OVERVIEW OF AUSTRALASIAN
EARLY PHASE CLINICAL TRIAL
ENVIRONMENT
Much has been written describing the virtues of the Australian
regulatory system and how it can offer an attractive alternative to
well-prepared product developers, especially during the early part of
their clinical development programme. Indeed, ERA Consulting
provide some illustrative case studies in this pullout that will assist
the reader in understanding the advantages that the local regulatory
structure can make available.
However, Australia, and indeed New Zealand, offer medicinal
product developers much more than just an efficient regulatory
framework. Of paramount importance to those planning clinical
trials are the availability, suitability and interest of clinical
researchers with volunteer populations, whether that be healthy
people or those patients with the indication being researched, that
are motivated and accessible within ever decreasing timelines.
Australasia
Australasia is sometimes used as a term for New Zealand and Australia
together, in the absence of another word limited to those two countries.
Sometimes Papua New Guinea is encompassed by the term. Australasia,
with a combined population of around 25 million people of predominantly
European descent, but with sizeable Polynesian and Asian populations, is
ageing at a rate comparable to other developed countries. This means
that Australasia has a similar disease profile and incidence as those
countries from where the majority of clinical trial therapies are generated.
This is a broad conclusion and indeed there are several indications that do
differ in incidence, such as higher levels of respiratory disease - with asthma
being the highest in the world - or climate influenced conditions such as
melanoma. On the other hand, such prevalent illnesses do tend to be better
managed as well, thus sometimes limiting the size of a suitable trial
population. Infectious diseases are geographically distinct with conditions
such as Ross River Fever being mainly a local (i.e. Australian) disease.
Indeed seasonal disorders such as infectious disease, allergies, etc often
mean that the southern hemisphere can offer the developer an all-yearround trial opportunity when conducted in series with northern hemisphere
season.
Australasia is a small market with Australian Pharma accounting for
approx $9.4 billion (which includes complementary medicines and medical
devices) and represents only about 1.3% of the world market. This can
mean that the local patient population may not always get access to new,
early development stage products, such as might be available in larger
markets such as the US or Europe. This does create a genuine interest and
enthusiasm from clinicians and patients alike wanting to get access to
cutting edge treatments or, at a minimum, be part of finding a solution
for those conditions they may suffer from. This view is widely supported as
evidenced by many companies reporting good enrolment across all phases
of clinical trials where Australasia was part of their clinical trial programmes.
Early Phase Clinical Research Units
Of particular note is the recruitment success seen across the spectrum of
54 JCS
phase I-II trials conducted in the region over the last five to six years.
Typically, many such studies have focused upon healthy volunteers, with
six of the established Australian and New Zealand phase I units having, as
you would expect, significant databases of healthy male and female
volunteers, including sub-groups based on, for example, age and ethnic
origin. This is made easier with most units being centrally located in the
major Australian or New Zealand cities and close to higher education
facilities, tertiary hospitals and in some cases, access to large local General
Practitioner networks. Indeed a 2007 review of the phase I units suggested
that there were around 170 beds in specialised, dedicated Phase 1 units
accounting for an industry revenue of over A$50million per annum with
over 75-80% of their business coming from the US, Europe and Japan, of
which over half was considered repeat business. The Q-Pharm article
elsewhere illustrates in more detail the type of expereince and capabilities
demonstrated by these units.
As well as such professional units, there is clearly an emerging second
tier group of units across Australia and New Zealand with good experience
in phase I studies but without the dedicated facilities of the main phase I
units. These units, predominantly part of tertiary teaching hospitals and
associated private clinics, are well positioned to contribute wholly or
partially to early phase studies, especially where subject confinement is
not a requirement, as this is one common restriction at such facilities.
Indeed, many do work co-operatively with local phase I units to which they
are comfortable to refer their patients when study designs may be too
demanding or labour intensive for them to run in their own clinics. With
their close relationships with their day-to-day patient populations this often
leads to a more personal service for patients thus better recruitment,
retention, and quality. Such groups offer sponsors more direct and efficient
access to educated and motivated patient populations. Therefore, with the
recent trend for more and more early phase studies to be conducted in
target patient populations, the strength of such an active researchorientated, second tier of investigational sites ably positions Australasia as
a proven option for sponsors in their early phase of development.
Clinical Network Services (CNS) notes that almost a third of its phase
I/II studies are patient studies and is a strong advocate of using these
specialist, niche therapeutic research groups that include respiratory groups
such as P3 in New Zealand and the Mater hospital, Brisbane, the Pain and
Anaesthesia Research Clinic (PARC) in Adelaide, numerous oncology groups
across the entire region, Queensland Paediatric Infectious Diseases (QPID)
Laboratory, Brisbane and the newly launched Prostate Cancer Research
Centre at the Princess Alexander Hospital, Brisbane, to name but a few.
For international sponsors having access to such a wide variety of site
and patient resources, but may have not conducted studies in Australasia
previously, distance and time differences can be a worry and may in some
minds mitigate the many obvious advantages of the region. However, it
would be fair to say that where the decision was taken to use Australiasia,
many companies return with Australasia forming a core component of
much of their development strategies supported by investment in forward
planning and feasibility of studies working with trusted affiliates or
www.jforcs.com
specialist CROs. The value of local expertise cannot be understated and is
a key component in managing anxiety driven by distance and timezone.
Local Partnering Essential
Using a trusted local partner is also of great value when one considers the
options available in Australasia as described earlier in this article. It is to
be expected that local specialists will know their local market better than
many internationally located sponsors. Specialists such as local niche CROs
depend upon knowing the capabilities and performance of phase I units
or the plethora of therapeutically focused investigational sites. Clinical
Network Services (CNS) is one such organisation, who with over 10 years
advising clients on which sites best suit their needs, including populations,
resources, timelines, etc, are experts in liaising with local sites and preparing
effective site strategies to meet ever decreasing product development
timelines and budgets. CNS is an Australia-based, full service contract
research organisation (CRO) providing clinical management support and
services to the healthcare community, particularly during the early phase
clinical development of their products. CNS has established itself as
Brisbane’s only headquartered clinical management company working
both nationally with dedicated phase I units and hospital groups, as well
as internationally with its strategic partners, particularly in New Zealand.
Over the last five years of its 10 year history, CNS has expanded its
services from traditional core CRO activities such as study management
and clinical monitoring to providing a full range
of services from initial protocol/IB development,
through study startup and third party
management, such as analytical laboratories,
selection of sites with capacity to run early phase
(0 – 2a) and proof of concept studies, monitoring
and over study management concluding with full
Data Management/Biostatistics and Clinical
Study Report writing.
of infectious and non-infectious samples for transit must be performed by
properly trained and certified staff and though many international
shippers are experienced in shipping such products, unpredictable
transport issues can be avoided by using local laboratories. Indeed, most
laboratories have their own national courier networks which ensures
appropriate packaging and timely delivery of samples to the assessing
laboratory.
Also when considering the analytical capabilities in Australia, and where
the sponsor is still in the pre-clinical phase, several groups have
internationally accredited pre-clinical services that may be attractive to
sponsors where their local partners may have timeline delays or where cost
is an issue. This is discussed in more detail in the article here by TetraQ.
Data Capture
In regards to fast data access, especially where go/no-go decisions in
ascending dose studies are required, Australia is very familiar with the
international electronic data capture systems commonly used. Indeed,
recent surveys have shown that upwards of 98% of Australian sites have
good internet access and have used such EDC systems. That said, many
single site phase I studies rarely require this complexity of live data
reporting and many of the phase I units and CROs are very familiar with
timely collection of safety data and providing necessary tabulations to
Data Safety Monitoring Committees or similar. Furthermore, Australia has
also responded to early phase data management
needs where groups such as CPR Pharma have
great experience in meeting sponsors’ data and
analytical needs in these small specialist studies.
Continuing broadly from data capture and
management, it would be remiss not to mention
Australasia’s standing at the front line of
technological applications in research. The
convergence of many new and evolving disciplines
in medicine, IT and science is bringing about a
fundamental paradigm shift in the way medical
research, drug research and, ultimately, patient
care is undertaken. Translational medicine and in
particular bioinformatics has become a leading capability in Australia and
again, support services in this area are emerging as highlighted by QFAB
in these pages.
“Continuing broadly from
data capture and
management, it would be
remiss not to mention
Australasia’s standing at the
front line of technological
applications in research.”
Ancillary Services
Another consideration for international sponsors
is how to manage theancillary activities that are
critical in the success of the trial itself. To some, this may add a level of
complexity to conducting studies so far away. Considerations include
where to package product; how to handle frozen samples and their
shipment to analytical laboratories; how to access safety data and analyse
in a timely manner (even more so when assessing Dose Limiting Toxicities
(DLTs) in a single ascending dose (SAD) phase I study) and many more. It
should not be surprising to the reader that as well as a growing group of
early phase sites, there has also been an accompanying growth in those
support groups, many of whom also write here.
Secondary Manufacturing for Clinical Studies
Whilst initial manufacturing tends to be more locally managed and
outsourced by sponsors, there are secondary manufacturing capabilities
in Australia. This can be useful where products have a short shelf life, such
as some biologicals, or where local labelling needs cannot be
cost-effectively met at the primary manufacturing sites. However, there is
an emerging drug manufacturing industry in Australia as described in BPA’s
article elsewhere in this pullout.
Laboratory Management
Australia’s local and central laboratories are strongly preferred by
Australian investigators in order to avoid loss of or damage to test samples
and reduce wastage of time and sample tissue. Such preferences may be
more prevalent in more specialist indications such as microbiological
testing in Cystic Fibrosis patients, where investigators are used to the
quality and reporting of their local laboratories. Furthermore, packaging
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Conclusion
Australasia has been a key contributor to global phase IIb – IV studies over
the years. The region has also emerged as a responsive and innovative
option in earlier phase studies as well, not only with respect to the number
of experienced and highly capable phase I units such as Q-Pharm and
ACRO, but also as seen by the enthusiasm of key opinion leaders, specialist
research groups and most importantly their patient populations. Where
sponsors partner with knowledgable and capable partners, efficient and
reliable strategies are available in Australasia to sponsors of all types, and
when local ancillary services are also considered, Australia and New
Zealand offer an increasingly time, delivery and cost attractive, “one-stop
shop” in early phase research. I
Russell Neal has almost 20 years' experience
in the healthcare industry. He moved with
Quintiles UK to Sydney in 1994 before moving
to Singapore in 1999. In 2003, Russell
returned to Australia following three years as
a Regional Training Manager Asia Pacific and
is currently Chief Operating Officer at Clinical
Network Services (CNS).
JCS 55
CONDUCTING EARLY PHASE
CLINICAL TRIALS IN
AUSTRALIA
Phase I clinical trials are a critical stepping stone in product development
pipelines for biotechnology and pharmaceutical industries. These trials are
crucial because they are used to establish the safety and tolerability of new
products in humans and thereby determine if they are safe to proceed into
further clinical testing. As such, phase I clinical studies are the first point in
clinical development where biotechnology and pharmaceutical companies
make the crucial ‘go/no go’ decision. Given the importance of this decision
and the high costs associated with continued clinical development, it is
imperative that phase I trials be conducted in an efficient and cost
effective manner without compromising quality. Fortunately, as will be
shown in this article, Australia offers an attractive proposition for
conducting early phase clinical trials from quality, efficiency and economic
perspectives.
Why choose Australia for early phase clinical trials?
Australia has an established, professional and world-class industry for the
conduct of early phase clinical trials. Importantly, the early phase clinical
trial industry in Australia offers a number of competitive advantages
including:
•
•
•
•
•
Low average cost (very cost competitive compared to U.S. and
Europe based providers)
High quality of work
Fast regulatory times / efficient regulatory system
High percentage of clinical trials completed on time
Highest standards of care and medical infrastructure
Australia has also been recently recognised as a safe location for
contract research services outsourcing. In particular, Australia has:
•
•
•
High levels of IP protection
Low risk destination with respect to
- Infrastructure
- Legal system
- Economic stability
- Human Capital
- Geopolitical factors
Mature pharmaceutical market
Importantly, trials conducted in Australia meet international standards,
such as those of the US FDA. This is because Australia’s early phase clinical
research centres conduct their studies according to ICH-GCP guidelines. It
is important to note that ICH-GCP guidelines were originally developed
with consideration of the current good clinical practices of the European
Union, Japan, and the United States, as well as those of Australia, Canada,
the Nordic countries, and the World Health Organization. As such, Australia
has a longstanding history of recognised and respected good clinical
practices. As a result, many clinical studies conducted at Australia’s early
phase clinical research centres, have been accepted internationally for
submissions to regulators.
56 JCS
The regulatory pathway in Australia – efficient and thorough.
Early phase clinical trials conducted using “unapproved therapeutic goods”
in Australia, that is, goods which have not been evaluated by the
Therapeutic Goods Administration (TGA) for quality, safety and efficacy
and entered into the Australian Register of Therapeutic Goods for general
marketing, are required to make use of the Clinical Trial Notification (CTN)
or Clinical Trial Exemption (CTX) schemes. This is because such products
are considered experimental, and do not have general marketing approval.
Such goods also include medical devices. There are a number of avenues
in the Therapeutic Goods Legislation via which “unapproved” goods may
lawfully be supplied. The CTN and CTX schemes provide two of these
avenues for access.
The choice of regulatory path, CTX or CTN, is the sponsor’s selection
and will determine the type of review process to be undertaken. CTX
involves review by the TGA of ‘information’ about the product provided by
the sponsor and can occur concurrently with the review of the protocol by
the local Human Research Ethics Committee (HREC). The ‘information’
includes the overseas status of the investigational product, proposed usage
guidelines, a pharmaceutical data sheet, a summary of the preclinical data
and clinical data. CTX is the pathway by which some novel new products
(especially biological agents) may proceed, particularly if they have not
been previously reviewed by a competent Regulatory Agency (e.g. FDA,
EU). In general, sponsors prefer CTN, but several trials are processed
through the CTX route.
For clinical studies being submitted by the CTN route, the local HREC is
responsible for assessing the scientific validity of the trial design, the safety
and efficacy of the medicine or device and the ethical acceptability of the
trial process, and for approval of the trial protocol. For phase 1 clinical trials
being submitted by the CTN route at Q-Pharm, the HREC require review of
the toxicology and Investigational Brochure by a demonstrably
independent reviewer. This review can occur in conjunction with the
submission process however the report must be available to the Clinical
Trials Protocol Sub-Committee (Scientific sub-committee of the HREC) by
the time it meets. Toxicology in this instance means the standard array of
preclinical testing. It is sufficient to provide the IB to the HREC, but some
independent evaluators may request additional details on the preclinical
data, especially if there are concerns. The independent reviewer can be
chosen by the sponsor, and is not required to be an Australian.
Providing the HREC were willing to review the protocol under the CTN
system, they would make a decision as to whether or not the trial was
ethically acceptable, and it is this advice that is communicated to the TGA
through the CTN form. Following acknowledgement of receipt of the CTN
form by the TGA, the trial may then commence.
Finally, clinical trials must be sponsored by an Australian entity
(company, institution or individual). If clients don’t have an Australian
subsidiary or affiliate, the sponsor can be a CRO that is contracted for the
purpose. Q-Pharm recommends that foreign clients engage an
independent CRO to fill the role of sponsor because under GCP there are
distinct obligations and responsibilities for the Sponsor’s representative
and the Investigational Site.
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The value of dedicated early phase clinical centres?
In Australia, early phase clinical trials are normally undertaken in dedicated
centres that are appropriately equipped for the specialised monitoring and
the high degree of surveillance required. As Phase I studies are normally
the first time the drug has been exposed to humans, the potential
associated risks mandate a high degree of surveillance of study volunteers
(as shown in Table 1). Given the intensity of monitoring and subject
surveillance required, it is easy to see why phase I studies are best
conducted in dedicated centres that are appropriately experienced, staffed
and equipped.
These clients come from the Pharmaceutical, Biotechnology and Device
Industries (Figure 2). This is why Australia’s early phase clinical research
centres have a broad base of experience with different investigational
product types. While the majority of clients approach providers directly for
clinical trial services, a significant number of projects are also brought to
these sites via clinical research organisations, as shown by the breakdown
of clients by sector for Q-Pharm (Figure 2).
Figure 2: Clients by industry sector for Q-Pharm
Table 1. Typical schedule of events for assessment of a volunteer in a Phase 1
study (not including pre-dosing assessments or assessments after 6 minutes postdose).
Event/Assessment
Design commenced
Time post dose
t=0
PK sample - 1 minutes post-dose
1 min
Post-dose Observations
(ECG, Temp, Pulse, Blood Pressure, Resps, sO2)
1 min
Adverse Event check
1 min
PK sample - 2 minutes post-dose
2 mins
Post-dose Observations
(ECG, Temp, Pulse, Blood Pressure, Resps, sO2)
2 mins
Adverse Event check
2 mins
PK sample - 4 minutes post-dose
4 mins
Post-dose Observations
(ECG, Temp, Pulse, Blood Pressure, Resps, sO2)
4 mins
Adverse Event check
4 mins
PK sample - 6 minutes post-dose
6 mins
In order to meet the demanding requirements of early phase clinical trials,
Australia’s early phase clinical research centres have specialised facilities.
By way of example, the Q-Pharm facility includes an 18 bed Phase 1 clinic
with telemetry, dedicated subject recruitment and outpatient facilities, a
24 bed clinic for Bioequivalent/Bioavailability studies (which can also be
used for Phase 1 or 2 studies), data management & QA units, secure
pharmacy, PC2 laboratory, minor procedures room, an extensive database
of volunteers, and a comprehensive network of clinical associates.
Client base of Australia’s early phase clinical research centres
Australia’s early phase clinical research centres service a truly international
market. In 2007, the industry generated annual revenue in excess of
$AUD50 million. The majority of these earnings were from overseas
sources and this international market share is increasing each year. For
example, during Q-Pharm’s years of operation, it has grown from a
company servicing Australian clients only, to a company whose majority
of clients are based overseas (Figure 1), and Australia’s other early phase
clinical trial service providers have reported the same business mix with
many international clients returning for repeat business.
Figure 1: Clients by location for Q-Pharm
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Experience and Capabilities of Australia’s Early Phase Clinical
Research Centres – Q-Pharm as an example.
Q-Pharm specialises in the conduct of early phase clinical trials and
bioequivalence and bioavailability studies. The company has more than
seven years experience in healthy volunteer and patient studies and during
that time its personnel have been responsible for the conduct of over 170
studies (and over 300 studies as Q-Pharm or its progenitor organisation).
Many of the clinical studies conducted at Q-Pharm have been accepted
internationally for submissions to regulators in Australasia, Europe and the
Americas. Like Australia’s other early phase clinical research centres,
Q-Pharm has a history of successful regulatory inspections and many client
audits. Inspections have come from North America (FDA inspection in
2007), South America (ANVISA in 2003, 2006 and 2008) and Australia.
For all early phase clinical research centres in Australia, alliances and
affiliations are key to a sites ability to successfully conduct these crucial
studies in a safe operating environment. For example, Q-Pharm is located
on the campus of one of the largest tertiary care teaching hospitals in the
Southern Hemisphere providing crucial access to emergency care, specialist
clinicians and potential volunteers. Q-Pharm also enjoys a strategic alliance
with TetraQ, providing the facility to undertake bioanalytical services.
CASE STUDIES
First-time in human studies
Australia’s early phase clinical research centres are well experienced with
conducting pivotal ‘first time in human’ (FTIH) clinical studies. Some
examples of FTIH studies conducted at Q-Pharm are provided in Table 2.
While the majority of these studies have proceeded via the CTN pathway,
some higher risk agents, particularly biologicals, have utilised the CTX
pathway. Of those studies processed via the CTN pathway, most have
been approved in a single round of HREC review, however some have
required multiple reviews in order to obtain ethical approval. These
examples highlight the notion that even though the regulatory pathway
in Australia can be efficient, it still operates at the highest standard (in line
with international and local requirements) in order to ensure the safety
and well-being of potential study volunteers is protected.
JCS 57
Table 2: Examples of experience with First Time in Human Clinical Trials at Q-Pharm
Client
Study type/
Subject type
Product type/
Route of administration
Regulatory Pathway (No. of
HREC review rounds required)
Outcome
AU biotech
Dose Escalation / HV
Biological + radiolabelled / IV
CTX
To Phase 2
AU biotech
Dose Escalation / P
Small molecule / IV
CTN (1)
IV to Oral
US biotech
Dose Escalation / P
New class biological / IV
CTN (3)
M&A deal executed
US academic
Dose Escalation / HV
Vaccine / IM
CTN (+IND*) (1)
To next phase
UK pharma
Dose Escalation / HV
Small molecule / Oral
CTN (4)
Trial suspended
AU academic
Dose Escalation / HV
Vaccine / IM
CTN (1)
To next phase
US pharma
Dose Escalation / HV
Small molecule / Oral
CTN (1)
Single Ascending Dose to
Multiple Ascending Dose
US pharma
Dose Escalation / HV
Peptide / SC
CTN (1)
Current
US pharma
Single dose / HV
Small molecule / Oral
CTN (1)
To next phase
US pharma
Dose Escalation / HV
Biological / IV
CTN (1)
Current
# - CTN path only with Expert, Independent Toxicology Review
KEY:
AU = Australia
US = United States
UK = United Kingdom
HV= Healthy Volunteer
P = Patient
IV = Intravenous
IM = Intramuscular
SC = Subcutaneous
Japanese Bridging studies
Q-Pharm recently identified the area of Japanese - Caucasian bridging
studies as a niche area for Australia’s early phase clinical trial industry. As
such, the company has conducted bridging studies for a client that
operates in the Japanese pharmaceutical market where Japanese subjects
were matched to Caucasians for gender and body weight. To ensure these
studies were successful, Q-Pharm put specific measures in place including:
•
Established large subject database of Japanese volunteers
•
Employed specific support staff
-Japanese nurses
-Nurses fluent in Japanese
-Japanese support officer providing interpretation service
which is available for volunteers
•
Designed Japanese specific menus
This case-study highlights the reality that many early phase clinical studies
require unique measures to be put into place in order for them to succeed.
However, it is normally only in the context of a dedicated phase I centre
that such measures can be accommodated.
Patient studies - Oncology
Q-Pharm has experience in conducting early phase clinical studies in
patients such as in the oncology setting. These studies are performed in
collaboration with local specialist clinicians from whom the patients are
recruited. Close collaboration with these clinicians is crucial to the success
of these types of studies given the health status of the patient volunteers
and their already established relationship with their treating clinician. As
such, sharing of trial related activities between the dedicated early phase
clinical research centre and the hospital clinic is standard practice. For
example, in a recent oncology study in patients with advanced solid
malignancies, the hospital clinic conducted recruitment, screening (e.g.
pathology, radiology), and outpatient activities (eg follow up visits). To
complement this, Q-Pharm conducted trial activities such as confinement
58 JCS
CTN = Clinical Trial Notification
CTX = Clinical Trial Exemption
(scheduling), pharmacy (study drug preparation), dosing, laboratory
(pathology, study specific pharmacokinetic sampling and analysis), and
after hour medical coverage.
Summary
Due to the current global financial crisis, sponsors are now more than ever
looking to conduct clinical trials in a cost effective manner without
compromising quality. Fortunately for these clients, sites such as Q-Pharm
in Australia offer an attractive proposition from both a quality and
economic perspective. Quality-wise, Australia’s regulatory processes
ensure studies are set up and conducted in an appropriate and recognised
setting to the highest standards of clinical practice. The regulatory
pathway in Australia is efficient and very well established which ensures
that the data generated from these studies is acceptable for submission
to regulatory agencies worldwide. For example, studies conducted in
Australia have been used to support marketing licensing applications in
the United States (FDA) and Europe (EMEA). When this quality advantage
and timeline efficiency is combined with the cost-effectiveness of
conducting clinical trials in Australia, it is not difficult to see why Australia
is becoming a key provider of contract early phase clinical research services
to the international market. I
Nathan Martinez, PhD, is Executive Officer at Q-Pharm
and is responsible for business and corporate
development activities. Dr Martinez has numerous years
experience in drug development from product design and
pre-clinical testing through to managing Phase III
studies. He gained his PhD in medical immunology at
the Walter and Eliza Hall Institute of Medical Re search,
has a post-graduate qualification in drug development,
and is ACRP CCRC certified. Prior to joining Q-Pharm, he
worked as a post-doctoral scientist in vaccine design and pre-clinical testing,
managed cell-therapy based clinical trials and associated basic research, and
also worked as a project manager and group leader at a GMP facility.
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AUSTRALIA SAYS G’DAY TO
CLINICAL TRIALS!
Australia offers a number of significant advantages as a site for
clinical trials one of which is a clear, affordable and uncomplicated
regulatory environment. There is a straightforward and rapid
regulatory process for the approval of clinical studies for most
investigational medicinal products, including biologics in some cases.
Also, for initial ‘first-in-man’ studies there is no requirement for the
trial material to be made under current Good Manufacturing Practice
(cGMP). All clinical research in Australia is conducted in accordance
with current international standards of Good Clinical Practice.
Through a series of scenarios this article will outline the regulatory
pathways for clinical trials in Australia. Although these examples are
hypothetical they do reflect the established experience of companies
operating in Australia and serve to illustrate regulatory requirements in a
number of different situations. For an overview of the regulatory steps
toward gaining approval to conduct clinical research in Australia, refer to the
schematic in Figure 1.
Figure 1. Schematic of the regulatory pathways governing clinical trials in
Australia (see Table 1 for abbreviations)
Table 1: Abbreviations
cGMP
CTA
CTN
CTX
DNIR
FDA
HREC
IB
IBC
MHRA
NLRD
OGTR
TGA
60 JCS
Current Good Manufacturing Practice
Clinical Trial Application
Clinical Trial Notification scheme
Clinical Trial Exemption scheme
Dealings NOT Involving Intentional Release
Food and Drug Administration [US]
Human Research Ethics Committee
Investigators Brochure
Institutional Biosafety Committee
Medicines and Healthcare products Regulatory Agency [UK]
Notifiable Low Risk Dealing
Office of the Gene Technology Regulator
Therapeutic Goods Administration
SCENARIO 1: SMALL-MOLECULE PHARMACEUTICAL IN LATE STAGE
DEVELOPMENT
A small-molecule pharmaceutical is in the late stages of development. The
US Company wishes to include several Australian sites in a pivotal, phase III
clinical trial.
The appropriate regulatory pathway for this clinical trial is the Clinical Trial
Notification (CTN) scheme. Under this scheme the approving authority is the
Human Research Ethics Committee (HREC) of the institution or organisation
at which the clinical trial will be conducted. HRECs are independent
committees affiliated with hospitals and other organisations conducting
clinical research. The agency responsible for regulating medicines in Australia,
the Therapeutic Goods Administration (TGA), is notified under this scheme
but no approval is required.
The sponsor of the trial must be an Australian entity so the USA-based
Company without an affiliate in Australia must retain an Australian CRO or
other such organisation to submit the application and sponsor the trial on
their behalf. The application package consisting of information on the
product, the trial, the trial site, various certifications and the Investigators
Brochure is submitted to the HREC in advance of a planned HREC meeting
date. A scientific/technical sub-committee usually performs a review of the
quality and non-clinical data of the proposed study and then passes a
recommendation on to the HREC. The HREC then meets to conduct a formal
independent ethics review, to generate queries to the investigator if necessary,
and finally to grant an ethics approval.
A [current] fee of 260 AUD is paid to TGA as the notification is filed for
each of the trial sites. Acknowledgment of notification is provided by TGA
within 10 days but there is no requirement for the Company to wait and the
trial can commence once the fees are paid. Under the CTN scheme the TGA
is only notified regarding the clinical trial however, TGA has the authority to
put a hold on clinical trials in Australia due to safety or other concerns.
Summary:
The CTN scheme provides a relatively rapid and simple path to clinical trial
approval. Providing scientific and ethical review, institutional HRECs are
responsible for approving clinical trials. The TGA collects a modest fee for the
notification and would normally take no action regarding the trial information.
SCENARIO 2: NON-CGMP BIOLOGICAL IN ‘FIRST-IN-MAN’
PHASE I TRIAL
A small biotech company is developing several related biological medicines.
Pilot-phase manufacturing of the candidates is to a high quality but in a
facility that is not GMP certified. The Company requires some initial clinical
data to narrow the field of candidates and secure and extra round of
funding.
In Australia there is a provision for initial “first-in-man” clinical studies to
be conducted with material that is not manufactured according to cGMP.
This is in recognition that at early stages of development manufacturing
processes are not fully developed and validated. It is especially pertinent to
biological medicines where significant manufacturing changes are expected
to occur during development. Of course, to be used in a clinical trial, the
investigational material must be of documented quality and appropriate
non-clinical data must be available.
This approach to manufacturing requirements is significantly different to
that of Europe where EU legislation mandates that all investigational
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medicinal products are manufactured according to EU cGMP. There may
be some flexibility pertaining to the manufacturing process but the facility
is absolutely required to be GMP licensed. In the US, FDA allows a
somewhat flexible and less onerous approach for phase I products, but
cGMP still applies.
As with 95% of applications in Australia, this clinical trial could be
approved through the CTN scheme. If the institutional HREC determines
that it has sufficient expertise to assess the quality and non-clinical data
supporting the application then it can approve the trial. Alternatively, if
the HREC determines that it does not have sufficient expertise or that the
trial would be ‘high-risk’ then it can defer reviewing the application to the
TGA through the Clinical Trial Exemption (CTX) scheme.
If the information in the Investigators Brochure is comprehensive then
the application has a better chance to be reviewed by the HREC under the
CTN scheme.
Summary:
In Australia, “goods prepared for the initial experimental studies in human
volunteers” are not required to be manufactured according to cGMP. There
is also the possibility of clinical trials involving somewhat complex
medicines such as biotech products to be approved through the rapid CTN
process.
SCENARIO 3: CELL THERAPY
A UK company is developing a human cell therapy product.
Scientific Advice
Appropriately, an early step in seeking approval for a clinical trial involving
an advanced medicine such as a cell therapy is to seek scientific advice
from the pertinent regulatory agency. The TGA is open to meeting with
companies to discuss scientific and regulatory issues, and provides this
service free of charge. In contrast, for example, the Medicines and
Healthcare products Regulatory Agency (MHRA) in the UK charges up to
£4,542 for providing scientific advice.
The Clinical Trial Exemption (CTX) scheme
In Australia, the regulatory pathway for a clinical trial involving a
‘high-risk’ product, an advanced therapy or a gene therapy is the Clinical
Trial Exemption (CTX) scheme. An application consisting of summaries of
quality, non-clinical and clinical data along with the information on safety
(adverse event experience) and on proposed usage of the product, and
the Investigators Brochure is submitted to the TGA. The applicant must
wait until written approval is provided from the TGA, as well as HREC
approval, before starting the trial.
TGA first evaluates the application and determines if there are any
issues with the proposed use (“usage guidelines”). The CTX review period
is 30 or 50 business days depending on the content of the package
submitted. Where there are no clinical data the 30 day review may apply.
The fee for the 30 and 50 day CTX review is currently 1,240 AUD or 15,300
AUD respectively.
During review of the CTX dossier questions and clarifications are
addressed to the applicant through one or more requests from TGA with
stipulated times for the applicant to respond. The evaluation clock stops
until a full response to the request is received by the TGA. Any requests
that have not been answered completely may appear in the assessment
report generated by the TGA at the end of the evaluation period. Any
outstanding questions must be satisfactorily answered by the applicant.
The applicant must wait until written approval is provided from the TGA
before starting the trial.
A hallmark of the CTX application process is the flexibility of the TGA
in addressing objections and working with the applicant to develop
solutions. As an example, at the TGA’s discretion, an applicant can be
allowed additional time in which to address issues regarding an advanced
therapy product without termination of the review of the procedure.
62 JCS
The flexible approach of the TGA can be contrasted with that of the
MHRA, which allows only 30 days to respond to any deficiencies in a clinical
trial application (CTA). If the applicant cannot address the deficiencies
within this timeframe the application is rejected and this rejection is
recorded in the pan-European EudraCT database. In addition, the
situation in Australia contrasts with that in the US, where deficiencies in
an IND application that cannot be addressed rapidly can lead to a “clinical
hold” being issued.
Assuming that any objections have been resolved the TGA will provide
written authorisation for the CTX. The applicant must in parallel secure
HREC approval for the institutions where the trial will be conducted; in
some cases the TGA will provide comments to assist the HREC(s) in coming
to a decision.
SCENARIO 4: GENETICALLY MODIFIED CELL THERAPY
A company is developing a genetically modified cell therapy product.
As a genetically modified viable cell therapy in Australia the product
would also fall under the category of a genetically modified organism
(GMO). Thus the product and clinical trial information would need to be
reviewed by an Institutional Biosafety Committee (IBC), and would require
a licence from the Office of the Gene Technology Regulator (OGTR). As
with other advanced therapies, the appropriate regulatory pathway for this
product is a CTX application to the TGA, as well as approval from the
relevant HREC(s).
Clinical trials involving genetically modified cells or involving gene
therapy must be reviewed by a properly constituted and accredited IBC.
These independent committees composed of experts and lay people are
associated with research organisations and generally meet 4 - 12 times
per year. The applicant wishing to conduct the clinical trial must submit a
package describing the GMO to be used in the trial as well as the trial itself.
The application must also include a biosafety and environmental risk
assessment and management plan.
The application package should be submitted several weeks ahead of
a scheduled IBC meeting. The length of time to evaluate the submission
varies substantially depending on the particular IBC and the complexity
of the application. The IBC can also request additional information from
the applicant in order to come to a decision.
A GMO product intended for use in humans in a clinical trial constitutes
a “Dealings NOT Involving Intentional Release” (DNIR). In this case the
applicant must obtain a licence from the OGTR before commencing the
trial. The OGTR has 90 working days to reach a decision on the application,
which includes the assessment made by the IBC. In common with other
reviewing bodies, additional information may be requested and this stops
the evaluation period until the applicant responds. The OGTR has a broad
remit to seek advice from experts and other bodies including the TGA in
order to reach a decision. If a positive decision is made, the applicant will
be issued a licence for up to five years covering the use of that GMO. With
the licence from the OGTR, the CTX authorisation from the TGA and the
HREC approval, it would be possible to commence the clinical trial.
Conclusion
As described in the above scenarios, Australia has a streamlined regulatory
system suitable for investigation of small molecules up to complex
genetically modified cell therapies. This well-defined landscape can
welcome clinical studies ranging from “first-in-man” phase I trials to
multi-center phase IV trials. Come down and say G’day! I
Dr Dianne Jackson-Matthews, Director of ERA
Consulting’s Australian office, was formerly Director of
ERA’s Washington DC office having spent 25 years in
the US including senior positions within the biotech
industry.
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AUSTRALIAN
BIOANALYTICAL EXPERTISE
FOR PRECLINICAL AND
CLINICAL STUDIES
Australia has a rich history of success in the drug development and
clinical trial industries. An essential part of that process is the
provision of quality bioanalytical services to meet the needs of both
the preclinical and clinical stages of development. The requirement
to conduct bioanalysis to a standard which will satisfy stringent
performance limits, such as those set out by regulators like the US
FDA, dictates that such providers must have significant expertise in
the field. Such laboratories are not only required to accurately
analyse large numbers of samples generated from clinical trials in a
reasonable timeframe, but must also be expert in bioanalytical
method development and validation.
Bioanalysis in Preclinical Testing
Preclinical drug development brings with it a whole set of bioanalytical
challenges and requirements. Many companies at early stages of drug
development are seeking indicative results for their lead compound and
they do not require, nor will they fund, extensive bioanalytical method
validation prior to sample analysis. For example, the result required from a
preclinical pharmacokinetic study conducted in rodents might simply be
an indication of whether the in vivo half life of the candidate drug is in the
order of “hours, days or weeks”, or preliminary information on the bioavailability of the compound following an oral or other extravascular dose.
Of course, even at early stage drug development, sponsors still need to
have confidence in the data provided to them. However, how can this be
attained without conducting extensive pre-study validation of the
bioanalytical method involved? Quite simply, the sponsor must have
confidence in the bioanalytical service provider and in the work conducted
by them.
Contracting bioanalytical work to specialist laboratories that are well
equipped, have experienced staff and are suitably accredited, with
appropriate quality systems in place, allows sponsors to have a reasonable
degree of confidence in the results provided to them, and allows those
results to be used as the basis for further decision-making in the drug
development process.
TetraQ is a preclinical service provider based in Brisbane, Australia. The
ADME/Bioanalytics laboratory of TetraQ is a recognised leader in
bioanalytical assay development and validation and is well equipped with
chromatographic equipment (LC-MS/MS, HPLC). The TetraQ ADME/Bioanalytics facility was the first laboratory in Australia to gain accreditation
with the National Association of Testing Authorities (NATA) in the field of
Research and Development, with a quality system that complies with
ISO/IEC 17025 (2005). It is also recognised for compliance to the OECD
Principles of Good Laboratory Practice (GLP), which allows its bioanalytical
results to be accepted internationally for regulatory review and provides a
high degree of assurance for TetraQ’s clients.
TetraQ’s R&D accreditation allows the flexibility to provide varying
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levels of analytical method validation depending on clients’ needs, from
screening assays (as might be required for early-stage preclinical
pharmacokinetic studies such as those described above), to comprehensive
validation for regulatory purposes.
Method Development and Validation
TetraQ has extensive experience in the development of chromatographic
assays for new and existing pharmaceutical and biotechnology products
(including peptides), and has an extensive list of validated assays on hand.
TetraQ conducts validation as necessary for preclinical studies; however
assays intended for use for the analysis of samples from human clinical
trials invariably require comprehensive validation prior to use. For such
studies, validations conducted by TetraQ meet the requirements of the FDA
Guidance for Industry on Bioanalytical Method Validation (May 2001).
Detailed reports are prepared for all comprehensive method validations.
Bioanalysis Using ELISA Methodology
The development of new biological and antibody-based pharmaceuticals
has led to an increasing requirement for the quantitation of these
compounds in plasma as part of preclinical and clinical experimentation.
These compounds are frequently not suitable for analysis by
chromatographic or LCMS/MS techniques, and are often quantitated by
Enzyme-Linked Immuno Sorbent (ELISA) Assays. Validation requirements
for ELISA assays differ from those for chromatographic methods, in that
additional specificity testing must be carried out to ensure the correct
molecule is being quantitated and the assay is free from interference due
to cross-reactivity of the antibody with other endogenous compounds. The
acceptance criteria for accuracy and precision of ELISA assays also differ
from those for chromatographic assays; the FDA Guidance on Bioanalytical
Method Validation outlines the specific requirements for ligand-binding
assays such as ELISAs, and these require careful interpretation by the
analytical laboratory responsible for the validation and conduct of these
techniques.
The TetraQ ADME / Bioanalytics facility is one of the few laboratories
in the Australia-Pacific region that is accredited to conduct bioanalysis
using ELISA methodology. TetraQ has successfully transferred preestablished ELISA assays into their laboratory and performed appropriate
levels of validation to ensure optimum assay performance. TetraQ can also
assist with the development of new ELISA assays, as long as an antibody
against the test compound is available. Immunogenicity ELISA assays,
such as those testing for the presence of human anti-human antibodies
(HaHa) in plasma samples following the administration of biological
pharmaceuticals such as humanised monoclonal antibodies, have also
been transferred into the TetraQ laboratory and used for the analysis of
samples from clinical trials conducted both within Australia and overseas.
Inflammatory markers such as interleukins are also often required to
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be quantitated in plasma samples from clinical trials involving the
administration of biological or antibody-based compounds. These markers
are measured by TetraQ using ELISA methodologies; in these cases TetraQ
procures commercial assay kits from reputable suppliers and conducts
pre-qualification of the methods, using quality control samples prepared
in-house, to ensure optimum assay performance and compliance with
international regulatory requirements.
Industry Affiliations
TetraQ has a strategic alliance with Q-Pharm Pty Limited, a clinical trial
provider also based in Brisbane (indeed housed in an adjacent building to
the TetraQ ADME / Bioanalytics laboratory) and which specialises in the
conduct of early phase (Phases I and II) clinical trials, and human
bioequivalence and bioavailability studies. TetraQ provides all of the
bioanalytical and pharmacokinetic services required by Q-Pharm, and
works closely with them to formulate the development and validation of
new bioanalytical methods as required.
Pharmacokinetic Analysis
TetraQ conducts pharmacokinetic analysis of concentration vs time data
from preclinical and clinical studies, on data generated in-house or by other
service providers. Analysis is conducted using WinNonLin software that has
been extensively validated using the comprehensive validation suite
purchased from the software supplier. Statistical analysis of the results of
bioequivalence studies is also available, with confidence interval
determinations conducted on pharmacokinetic parameters.
complete toxicological assessment of new drug entities must be conducted
and the compound shown to be safe enough for human administration
before their use in clinical trials. TetraQ provides these and many other
services to the Australian and international pharmaceutical and
biotechnology industries. The table below lists some of the preclinical
services offered by TetraQ.
Who are TetraQ’s Clients?
TetraQ’s clients are Australian biotech and pharmaceutical companies
(both ASX listed and private), universities and research institutes. TetraQ
also has international clients that are based in Japan, USA, Europe, UK and
Asia. As well as attracting new clients TetraQ has repeat business from
many established clients which indicates strong client satisfaction.
Conclusion
In conclusion, Australia has significant capabilities and expertise in
providing bioanalytical services for preclinical and clinical studies for the
Australian and international pharmaceutical and biotechnology industries.
TetraQ is a leading Australian provider of high quality bioanalytical and
preclinical services and is a ‘one stop shop’ for early stage drug
development. With world class facilities, state of the art equipment, a
strong commitment to quality and a highly skilled scientific and
commercial team, TetraQ is focused to provide tailored solutions to meet
clients’ bioanalytical and preclinical needs. I
Russell Addison is the Senior Manager of the ADME /
Bioanalytics laboratory of TetraQ. He has a PhD in
human steroid metabolism and analysis and has
extensive experience in drug metabolism,
pharmacokinetics and bioanalysis.
Other Preclinical Specialities
Of course, bioanalysis is only part of the overall preclinical pharmaceutical
development process. All new drug candidates require extensive testing in
a number of areas to demonstrate that they are effective and safe enough
to be progressed into human trials. For example, potential treatments for
pain or other neurological disorders require efficacy testing to ensure the
effectiveness of the compound in an in vivo animal model. In addition,
ADME/ Bio-analytics
Efficacy
Toxicology
Pharmaceutics
Contract Bioanalytics - Bioanalytical method
development, validation and sample analysis in
human and animal biological samples
-LC-MS/MS, HPLC, ELISHA, PAMPA assays
Proof of concept studied in
animal models of human
disease
Genotoxicity assays - Ames Test, Micronucleus
Test, Mouse Lymphoma Assay
Physicochemical
characterization
In vitro drug metabolism studies - Cyropreserved
hepatocytes, hepatic microsomes CYP450 screening,
metabolic stability and metabolite identification
Pain models - nociceptive,
inflammatory and neuropathic
Dose escalation and dose range finding studies
Solubility studies
In vivo bioavailability and pharmacokinetics studies
CNS models - Multiple
Sclerosis, Parkinson’s disease
Acute and repeat dose (chronic) toxicity studies
Stability trials
Toxicokinestics
Other models - diabetes,
obesity, allergic rhinitis,
pheblitis, cancer (through
partner)
In vivo safety pharmacology (including hERG,
respiratory and CNS)
Dissolution studies
Tissue distribution, plasma protein binding and plasma
stability studies
Both the ADME / Bioanalytics and Toxicology laboratories are recognised for compliance with the OECD Principles of Good Laboratory Practice.
64 JCS
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TRANSLATIONAL RESEARCH:
THE BIOINFORMATICS
CHALLENGE
The Queensland Facility for Advanced Bioinformatics, QFAB, (http://qfab.org) is a Queensland Government Smart State-funded initiative to provide advanced capability and
facilities in data management, integration and analysis for Australia’s growing biotechnology and health sectors.
Founded in early 2007, QFAB is providing high-end data integration and analysis for its partners and a growing base of clients. Its partners are The University of Queensland,
Queensland University of Technology, Griffith University, Australian eHealth Research Centre (a joint venture of CSIRO and Queensland Government), Queensland Department
of Primary Industries and Fisheries, Queensland Cyber Infrastructure Foundation, and the Australian Partnership in Advanced Computing (the latter now incorporated into
NCRIS).
The discovery and development of effective new and modern
therapies can be achieved using a translational research approach.
Translational research draws on the expertise of the biological
researcher, clinician, biostatistician and computer scientist to
discover the basis of disease and to translate that knowledge into
therapies. The collective interchange of ideas, concepts, language
and data represents a significant challenge which is being addressed
through the application of sophisticated bioinformatics and
integrated computational environments.
Translational Research
The drive to understand the mechanisms of disease is fundamental to
biomedical science, health practitioners and the pharmaceutical industry.
Not only does this hold the promise of the discovery of better drugs but
also the potential for more personalised medicine. Approaches to drug
discovery are being accelerated through the application of a methodology
known as translational research. This approach aims to understand the
molecular basis of disease linking together experimental approaches such
as gene expression, Genome Wide Association studies (GWAS) and
proteomics, with data from clinical trials and general patient information [1].
The NIH Roadmap for Medical Research outlines one of its objectives
as transforming the way biomedical research is conducted [2]. One of the
Roadmap initiatives, Biomedical and Computational Biology, is funding
the development of software and tools to link the clinician’s observations
with the discoveries of the researcher [3, 4]. Other groups around the world
are aiming to do similarly with specific software applications or through
software such as interactive workflow packages, for example Inforsense
[5] or IO Informatics [6], which link the various data and analytical
components.
Translational research faces two primary areas of challenge: at the
technical level, linking and visualising disparate data which may use
different or no ontologies and, at the social and regulatory levels, with the
need to maintain patient confidentiality through compliance with clinical
records privacy laws.
The Queensland Facility for Advanced Bioinformatics (QFAB)
QFAB is a Queensland collaborative initiative with a commitment to help
life science researchers unlock the full value of their research data through
the application of bioinformatics. It delivers advanced bioinformatics
solutions to enable the global efforts of biotechnology, research biology,
drug discovery and translational medicine. Contributions from QFAB
partners often leverage other initiatives including the ARC Centre of
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Excellence in Bioinformatics at UQ or the Microsoft QUT eResearch Centre.
As represented in Figure 1, QFAB provides specialised bioinformatics tools,
workflow technology, health data integration software, computational
resources and ICT experience. QFAB also operates mirrors of the UCSC
Genome Browser and ENSEMBL, and hosts public and proprietary datasets
federated via SRS. With transparent access to data and applications,
project-dedicated computation and storage, and the required
confidentiality, privacy and security, partners and clients carry out secure
in-silico discovery both on-site and remotely. In this article we will illustrate
by way of example some of the initiatives in translational research that
the Queensland Facility for Advanced Bioinformatics is involved in.
Figure 1: QFAB platform is built around a web service workflow engine that
integrates disparate data (top right) and tools (top left). The Health Data Integration
software (HDI) developed by the Australian e-Health Research Centre provides linkage to
patient records in different hospital data repositories while maintaining privacy and
providing private and secure access to an integrated virtual data repository. This enables
research and analysis on a larger scale than would be possible on the individual data
repositories alone.
CASE STUDY - KOALA CHILDHOOD OBESITY PROGRAM
The KOALA Childhood Obesity Program is led by Dr Gary Leong, a
paediatric endocrinologist and researcher who divides his time between
the Institute for Molecular Bioscience (IMB) and the Mater Children’s
Hospital. The Program is designed to improve the understanding of the
basis of childhood obesity and its metabolic complications in order to
develop effective interventions. This will be achieved by the integration of
studies in metabolism, genetics, environment (family and lifestyles),
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community influences and behaviour management. The understanding
of the genetic interactions with the environment will aid in targeting the
intensity of lifestyle-based interventions for children and families with
low-, medium- or high-risk genetic, clinical and/or community profiles for
obesity and its major complications, including type 2 diabetes,
cardiovascular disease and fatty liver disease. The research outcomes will
be translated into improved clinical practice for children with obesity.
The KOALA program brings together researchers from the University of
Queensland and a multidisciplinary clinic at the Mater Children’s
Hospital that includes medical, nursing, psychological and allied health
professional team members. The KOALA program is currently in a one-year
pilot study, with general practitioners from the Queensland South East
Alliance of General Practice referring 100 overweight children to the
program.
QFAB has developed a web portal [7] to capture data from
participating families, health professionals and researchers, and continues
to work with the project toward its goal of identifying biomarkers for the
future onset of obesity-related illnesses.
CASE STUDY - NUCLEAR RECEPTORS IN BREAST CANCER
Therapies that target the estrogen receptor have shown great success in
treating breast cancers that express this nuclear receptor [8]. Despite the
success achieved through targeting the estrogen receptor, the significance
of other nuclear receptors in breast cancer management has received little
attention to date. The Nuclear Receptors in Breast Cancer (NRBC) project
is focused on studying signalling pathways of all the nuclear receptors that
are expressed in breast cancers.
The objectives of this discovery research program are to identify the
nuclear receptor networks active in breast cancers and from these to select
receptors that may be targeted for treatment in patients whose breast
cancer does not express the estrogen receptor and for whom current
treatment options are severely limited. Since many nuclear receptors have
currently approved therapeutic drugs available to modulate their activity,
these potential targets may be readily explored in the clinic to determine
if current drugs can be combined with existing breast cancer treatment
options to improve outcomes for underserved patient groups.
The Chief Investigators of the NRBC project are drawn from virtually
every State in Australia and contribute complementary expertise in
hormone research, bioinformatics, high throughput analyses, human tissue
research, animal models and clinical endocrinology. With Professor Mark
Ragan, who leads the ARC Centre of Excellence in Bioinformatics [9] and
the Division of Genomics and Computational Biology of the Institute for
Figure 2: An example of a protein-protein interaction network built around the
pregnane X receptor (PXR). Visualisation of the network is performed using the
Cytoscape software [18]. The shapes represent different classes of proteins, the
colour relates to the differential gene expression between two clinical cohorts.
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Molecular Bioscience at the University of Queensland, QFAB is currently
building one of the most comprehensive collections of protein interaction
networks around Nuclear Receptors and their co-regulators to visualise
gene expression data and facilitate decision support (Figure 2).
CASE STUDY – AUSTRALIAN PROSTATE CANCER RESEARCH CENTRE
(QUEENSLAND)
A new initiative to establish the Australian Prostate Cancer Research Centre
- Queensland has the vision of developing a hub of prostate cancer
research in Brisbane focused on new therapeutics, predictive biomarkers
and treatment response indicators to inform and drive improved clinical
practice.
Headed by Professor Colleen Nelson, the Centre’s partners span several
disciplines, employing high-throughput genome-wide bioprofiling of
prostate cancer tissues to discover and characterise molecular mechanisms
underlying prostate cancer progression and therapeutic resistance.
Validation of the relevance of potential targets through evaluation of
expression of candidate genes on tissue microarrays will be carried out.
Pathways and networks will be elucidated using advanced informatic
approaches and laboratory investigation to characterise the function of
candidate genes associated with treatment resistance. These findings will
be used to identify potential targets for intervention, with creation and
evaluation of new therapeutics.
To achieve this vision requires a collaborative multi-disciplinary
translational team-based approach (spanning discovery science to clinical
evaluation), underpinned by leading edge technology. QFAB will be
providing a stabilised point of data access using grid technology to
combine files distributed across multiple institutions and heterogeneous
storage systems into a virtual local collection. Many of the Centre’s joint
projects will require large scale data analysis and compute power available
through QFAB’s established expertise in the fields of bioinformatics,
statistics and computer science.
CASE STUDY – INNOVATIVE WOUND MANAGEMENT
Professor Zee Upton is leading the Tissue Repair & Regeneration Program
within the Institute of Health and Biomedical Innovation at the
Queensland University of Technology. With participants from all States in
Australia, a new Collaborative Research Centre is being proposed to
improve wound healing, quality of life and cost-effectiveness of wound
care in Australia. The goals are to advance current knowledge of the key
aspects of chronic wound care and wound healing, and to translate this
knowledge to transform wound healing and wound management through
the development of innovative products and practices, delivering benefits
to both communities and industry.
A unique strength of the initiative is the integration of the diverse
elements contributing to wound management into a cohesive program of
research which reflects the combination of the key biological, materials,
medical, nursing, epidemiology, economics, health service delivery and
industry expertise of the participants. The outputs of the research program
will lead to markedly improved, evidence-based wound management, a
better quality of life for patients and a reduced burden on health services.
Advanced genetic, biochemical and metabolite-based biotechnologies
will be used to analyse an extensive library of sequential samples collected
from patients with chronic wounds. The data generated will be correlated
with matched clinical data, leading to a revolutionary advance in
fundamental knowledge of wounds and healing. State of the art
bioinformatics tools will be used to integrate and analyse this data, and
novel techniques developed to support data mining and association
studies. Exploration and visualisation tools from the Microsoft QUT
eResearch Centre [10] will be specialised to the wounds domain, and
integrated with the QFAB facilities. Dedicated local systems and the high
performance clusters of the Australian National Computational
Infrastructure are available to the Program. This will support the
JCS 67
development of new diagnostic and prognostic tests to inform and guide
decision-making by clinicians, new wound therapies and appropriate
delivery strategies, and the development of improved wound care practices
and strategies for prevention.
Perspectives
The future understanding of human health and disease resides in a
systems level approach to biology [11]. Systems biology focuses on
biological systems as a whole, combining the facets of an organism into a
collective view rather than looking at individual genes, proteins, or parts.
Systems biology underpins the development of translational research and
it is this integrated view of biology which will provide the answers to many
of the questions about the mechanism of diseases. This methodology
requires a multidisciplinary approach to deriving models of systems which
can then be tested experimentally.
Multidisciplinary science requires the biologically meaningful
integration of data recovered from heterogeneous platforms in, amongst
others, the genomic, proteomic and metabolomic domains. Deriving
computational models in-silico will accelerate the discovery process, but
they are just that, models, and without interactive testing will continue to
be useful as signposts only [12]. Validation of the models through wet lab
and clinical testing will ultimately lead to discovery.
Data integration and privacy present enormous challenges to the
biologist, the clinician, the biostatistician and the computational scientist.
The marriage of these disciplines to enable the collective understanding
of the nature of disease and, importantly, the specificity of the clinical
intervention required will one day deliver tailored medical solutions. The
fulfilment of this promise is still some way off although there is a
considerable global research focus in this area.
Significant funding is being directed to this endeavour [2] and
specifically into centres such as Informatics for Integrating Biology and
the Bedside, i2b2 [13], Dana Faber Cancer Institute [14, 15], Scottish
Universities Research Alliance [16], or in Australia, the Translational
Research Institute which is a joint project between the Queensland
Government, UQ and its Diamantina Institute for Cancer, Immunology
and Metabolic Medicine, Mater Medical Research Institute (MMRI),
Princess Alexandra Hospital and Queensland University of Technology [17].
QFAB is not itself a translational research institute, but it does help
scientists with access to the bioinformatics tools and computational
capability to carry out this type of research. Building on its strengths in
understanding and translating the needs of the researcher into the
language of the bioinformatician and IT professional, QFAB will continue
to develop its platform and skills. Continuing to grow from the experiences
gained through its role in the case studies outlined above it has a goal of
expanding its functional capability to include a chemical biology interface
which will integrate tightly into its bioinformatics platform.
This collective bioinformatics platform will then be available to the
researcher and, when combined with the linkages to clinical and population
studies, should provide the nucleus for accelerating translational research
in Australia. I
References:
1. Beaulah, S.A., et al., Addressing informatics challenges in Translational Research with
workflow technology. Drug Discov Today, 2008. 13(17-18): p. 771-7.
2. NIH Roadmap. Available from: http://nihroadmap.nih.gov.
3. McConnell, P., et al., The cancer translational research informatics platform. BMC Med
Inform Decis Mak, 2008. 8: p. 60.
4. Athey, B.D., Keeping up with Bioinformatics and Computational Biology - Where have we
been? Where are we going? First Annual ORNL Biomedical Science and Engineering
Conference 2009 March 18-19; Available from: http://portal.ncibi.org/gateway/pdf/
AtheyORNLTalk.pdf.
5. Inforsense. Available from: http://www.inforsense.com.
6. IO Informatics. Available from: http://www.io-informatics.com.
7. The Koala research portal. Available from: http://koala.imb.uq.edu.au.
8. Swaby, R.F., Sharma, C.G., and Jordan, V.C., SERMs for the treatment and prevention of breast
cancer. Rev Endocr Metab Disord, 2007. 8(3): p. 229-39.
9. ARC Centre of Excellence in Bioinformatics. Available from:
http://www.bioinformatics.org.au/.
10. Microsoft QUT eResearch Centre Available from: http://www.mquter.qut.edu.au.
11. Systems Biology Available from: http://www.systemsbiology.org.
12. Russel, J. and Davies, K., Eric Schadt’s Integrative Approach to Predictive Biology, in
Bio-ItWorld.com. 2009.
13. i2b2, Informatics for Integrating Biology and the Bedside. Available from:
https://www.i2b2.org/.
14. Kahvejian, A., Quackenbush, J., and Thompson, J.F., What would you do if you could
sequence everything? Nat Biotechnol, 2008. 26(10): p. 1125-33.
15. Poh, A., Integrating clinical and Genomics Data, in Bio-IT World Magazine. 2009: Digital
Issue March/April.
16. Scottish Universities Research Alliance Available from: http://www.sulsa.ac.uk.
17. Translational Research Institute Available from:
http://www.investbrisbane.com.au/News/News.aspx?ID=264.
18. Shannon, P., et al., Cytoscape: a software environment for integrated models of
biomolecular interaction networks. Genome Res, 2003. 13(11): p. 2498-504.
Jeremy Barker, MSc, MBA, GDCSP, Founding CEO of QFAB,
Brisbane, Australia, with over 20 years experience building
life science enterprises including director of four
biotechnology companies.
Dr Dominique Gorse is Technical Manager at QFAB with
over 18 years experience in information management and
mining in the biotechnology and drug discovery sectors.
QUEENSLAND
BIOTECHNOLOGY – RIPE
FOR THE PICKING
There are many regions around the world jockeying to become local
biotechnology powerhouses. Few, however, possess Queensland’s unique
environment for biotechnology growth.
Queensland is Australia’s second-largest state, encompassing tropical,
sub-tropical, temperate and desert climates. Located in the nation’s northeast, it is actively positioning itself as a modern, dynamic and progressive
21st Century economy.
Queensland’s biotechnology strategy
The Queensland Government understands that building a strong
knowledge economy is essential to future prosperity. This philosophy lies
at the very heart of its Smart State strategy.
Developing a thriving biotechnology industry is an integral part of
Queensland’s Smart State strategy. That’s why, in 2005, the Government
launched a 10-year strategic plan.
Developed in consultation with industry through the Queensland
Biotechnology Advisory Council, the plan sets out a vision and action plan
to accelerate growth and develop Queensland into a regional hub for
biotechnology.
The state is well on track to meeting its industry targets of 16,000
employees and $4 billion in annual revenues by 2025.
From a standing start a decade ago, Queensland’s biotechnology industry
now has around two dozen drugs from local biotechnology companies in
clinical trials.
In 10 years the number of publicly listed biotechnology firms in
Queensland has risen from two to 12, and both revenues and employee
numbers have jumped by a factor of six.
The overall market value of the state’s biotechnology industry is
projected to be $20 billion by 2025.
That outstanding growth is underpinned by the government’s efforts
to build a critical mass of world-class scientists and infrastructure across
Queensland.
World-class infrastructure
Over the past decade the Queensland Government has invested an
unprecedented $297 million in R&D infrastructure, leveraging a further
$580 million through its Smart State Innovation Fund.
That’s money well spent. Thirty-six new research institutes have been
established, providing researchers with enviable facilities that place
Queensland firmly on the map as a hub of globally-competitive research
and innovation.
Further infrastructure commitments in facilities like the Boggo Road
Ecosciences Precinct and the Translational Research Institute will create
more platforms for growth in the breadth and depth of the state’s research
capacity.
There is a real opportunity in Queensland to focus on our investment
in translational research and development, using our outstanding research
base as the engine to generate more effective healthcare services and a
stronger life sciences industry.
In fact, that’s already happening. The University of Queensland's
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Centre for Clinical Research (UQCCR) is a new $66 million facility designed
to bridge the gap between exponentially-expanding biomedical science
and the increasing complexity of modern patient care.
UQCCR offers a unique and exciting opportunity for new and
established investigators to pursue cutting-edge, clinically-relevant research
in a world-class facility on one of Australia's largest health campuses.
When it’s built, the Translational Research Institute, located in the
capital of Brisbane, will be a one-stop-shop for discovery, production,
clinical testing and manufacturing of new biopharmaceuticals.
Critical mass of scientists
The Smart State strategy is already paying dividends, attracting some of
the world’s top minds to Queensland. Perhaps the most internationally
renowned is Professor Ian Frazer, who discovered and developed the
world’s first cancer vaccine.
Professor Frazer isn’t the only Queensland researcher at the top of their
game.
Professor Mark Kendall from The University of Queensland has
developed a nanopatch that could soon replace needles as the preferred
method of delivering vaccines, includes those for malaria. Professor
Kendall’s work has won him the 2008 Amgen Medical Research Award as
well as a US$100,000 Grand Challenges Explorations grant from the Bill &
Melinda Gates Foundation.
Professor Michael Good heads the Queensland Institute of Medical
Research, the largest medical research institute in the Southern
Hemisphere. In 2008 Professor Good was made an Officer of the Order of
Australia for his invaluable work developing a vaccine for malaria, a disease
that kills as many as three million people every year.
But there’s more to Queensland than smart people and smart facilities.
Low-hanging fruit
Smart investors and big pharma are constantly scouring the biotechnology
world for low-hanging fruit.
They need look no further than Queensland, where the supply is
abundant - and mostly unpicked.
Queensland’s biotechnology research intensity is on par with the
world’s most research-intensive nations, based on the number of refereed
biotechnology-related publications per million of population. That
indicates a rich supply of fruit.
The amount of fruit already picked within a given biotechnology
industry depends of investment intensity – how much business expenditure
on R&D is happening relative to non-business expenditure on R&D.
Queensland’s investment intensity is quite low compared to other
biotechnology hubs, leaving plenty of opportunity for international
companies and investors to commercialise Queensland discoveries.
The state is not just rich in research – its biodiversity is almost unrivalled.
And how much better is it to pluck a chemically novel lead acting at a
biologically unexplored target than to be content with another me-too?
Queensland biotechnology offers more than twice as many investment
opportunities per capita compared to, say, the USA. More importantly,
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many of those opportunities are unique, offering the chance for investors
to back first movers in emerging fields.
The combination of its R&D strength, relatively low costs, competitive
environment and superb quality of life make Queensland an obvious target
for biotechnology investors.
Queensland’s tropical focus
Queensland’s unique location is an obvious advantage for biotechnology
companies and researchers focused on tropical discoveries.
The state is one of the few first-world economies with both a significant
tropical footprint and the capacity to undertake substantial tropical R&D.
The Australian Institute of Marine Science, near Townsville in the state’s
north, boasts the highest concentration of tropical marine scientists in the
world. James Cook University is also at the forefront of tropical
science research.
Other world-class facilities based in Queensland’s tropics include: the
Marine and Tropical Sciences Research Facility; the National Climate
Change Adaptation Research Facility; and the Australian Tropical Forest
Institute.
The Queensland Government recognises the enormous opportunity
that tropical science represents for the state. That’s why it developed the
Q-Tropics: Queensland Tropical Expertise Strategy 2008-2012, aimed at
stimulating jobs growth by building tropical knowledge industries.
It has also committed $19.5 million to a new Queensland Tropical
Health Alliance (QTHA), which will focus on reducing the burden of tropical
diseases in Queensland and surrounding regions.
The alliance is a joint venture between James Cook University, the
Queensland Institute of Medical Research, Griffith University and the
Queensland University of Technology.
The QTHA will interface through ongoing partnerships and linkages that
its members have with the Tropical Population Health Unit, the
Australian Biosecurity Cooperative Research Centre, the Australian Centre
for International and Tropical Health, the Australian Army Malaria Institute
and Queensland’s clinical health industry.
The proposed QTHA will undertake tropical health and medical research
and development in three key areas: drug and vaccine discovery and
development; diagnostics; and disease surveillance and control.
This is a substantial investment in Queensland’s tropical capabilities,
and will be leveraged by $33 million in cash and in-kind contributions from
the partnering institutions.
What the QTHA learns about dealing with biosecurity threats,
improving detection, diagnosis and treatment of tropical diseases, and
managing health risks associated with tropical disasters will vastly improve
health outcomes for people living in Queensland as well as those living in
tropical areas around the globe.
Industrial and agricultural opportunities
Queensland is also positioning itself as a formidable industrial and
agricultural biotechnology hub.
In response to spiralling greenhouse gas emissions and periodic crises
in the supply and price of fossil fuels, biofuels have emerged as an attractive
renewable energy alternative to conventional petroleum-based fuels.
With established feedstocks and significant expertise in metabolic
72 JCS
engineering, Queensland is well placed to be a world leader in the
development of biofuels and bio-based speciality chemicals.
The Queensland Government has made significant investments in
second generation biofuel research and development. While much of this
research is based on ethanol production, biodiesel and a range of other
fuels including hydrogen have also received significant research funding
support.
Recognising the potential of algae in the context of a biofuel strategy
and the need for Queensland’s heavy industries to reduce their carbon
footprint, the Queensland Government is supporting research and
development that aims to improve efficiencies and reduce the cost per litre
of algae biofuels.
In addition to world-class research expertise, Queensland has a number
of competitive natural advantages for algae biofuels production including:
prolific sunlight; abundant saline and brackish water; considerable tracts
of non-arable land; and a readily available source of CO2 from power
stations.
Queensland is a major centre for agricultural biotechnology in the Asia
Pacific, with particular expertise in tropical and subtropical agricultural
biotechnology. The state’s natural advantages enable tropical, sub-tropical,
and temperate crops to be grown. Queensland has extensive field trial sites,
laboratories and research institutes, an international clean and green
reputation, and a supportive regulatory and governmental framework for
biotechnology.
International alliances
Queensland’s biotechnology potential is staggering, but it can achieve only
so much with its relatively small population of 4.2 million. That’s why the
state is actively building strong strategic alliances of value to Queensland
bioindustries.
Although small compared to major international players such as the
United States, Queensland’s research is second to none. But the state does
have to work twice as hard to attract overseas markets when world markets
view Australia as too far away or too small.
It’s for that reason that we have developed strategic international
alliances with Washington State, South Carolina, British Columbia and New
Zealand, all of which are now helping to build Queensland’s global
biotechnology reputation.
Queensland researchers have 25 collaborations in development with
Washington State alone. I
Professor Peter Andrews is an eminent Queensland scientist and
bio-entrepreneur whose role as Queensland Chief Scientist involves
advising government on policy and economic development issues
associated with science, research and innovation.
Author of more than 100 publications and inventor of two patents,
he has led multifunctional scientific teams at research institutions
in Victoria and Queensland. Peter has been at the forefront of
initiatives to develop the Australian biotechnology industry and is
an active participant in the commercialisation of Australian science and research. Since
1985, he has founded, co-founded or been a director of more than 10 scientific companies.
He currently serves as a director of two Australian biotechnology companies.
Email: [email protected]
Website: www.chiefscientist.qld.gov.au
Phone: +61 7 3224 7630 or Facsimile: +61 7 3404 6975
www.jforcs.com
ENABLING A NETWORKED
AND COLLABORATIVE R&D
ENVIRONMENT
Recent reports by PriceWaterhouseCoopers (1), Deloitte (2) and in the
Harvard Business Review (3,4) address challenges that the biopharmaceutical industry is facing regarding patent expiration on existing
products and the failure of their current R&D business models to efficiently
bring innovative drugs to the market. The R&D challenges can be
summarised as follows:
•
•
•
•
•
•
•
Elucidate underlying disease mechanisms
Identify markers to distinguish between patients with similar
symptoms but distinct biological conditions
Identify targets that are amenable to therapeutic intervention
Identify clinical biomarkers: different treatments for different
patient subpopulations
Reduce both number and size of trials required to prove efficacy
Test the hypotheses underpinning the new molecules in man
as early as possible
Reduce R&D costs
its service offering, yet being responsible for managing the sub-contractors.
In both the one-vendor and preferred vendor model, the biopharma
company deals with one party which has advantages in terms of robust
sourcing governance, i.e. managing the business relationship between the
biopharma company and vendor. If the outsourced R&D process is quite
predictable and operationally focused, the two models can work well as in
the case of phase III/IV trials
However, there is now ample evidence in the industry that the onevendor model in which one organisation provides end-to-end services to a
biopharma company across several years, usually packaged as a strategic
alliance, does not always provide the expected cost efficiencies, time
savings or quality benefits. Biopharma companies need to stay in control
of their product development processes, avoid being locked into a longterm contract and accept that there are transaction or coordination costs
associated with selecting, and overseeing the performance of contractors.
Category Leaders
One trend is for companies to restrict the expenditure on R&D and
Marketing and Sales (M&S) by focusing the company’s efforts on a limited
number of therapeutic areas and diseases. Consequently, the aim of the
company is to become a (Global) Category Leader. Nonetheless, while this
strategy provides focus to the research and development efforts of a
company, it only emphasises the need to establish collaborative networks
with specialist academic and commercial researchers outside the
company.
Collaborative R&D Networks
In view of the breakdown of the current R&D paradigm and one-vendor
model, the trend is that companies are looking outside their company and
geographic borders to identify the appropriate capabilities and expertise
at academic institutions and commercial contract research services
providers having specialised know-how and technical capabilities. In other
words, they are looking for research institutes and CROs that are most
suited for a particular R&D process, task or activity or who can execute
functions that are highly specific or strategic. This is called the “best-ofbreed” or “multisourcing” model. It provides greater control to the biopharma company and delivers higher performance than “single” sourcing.
However, it also requires multiple vendor negotiations and, although risks
can be shared across multiple vendors, the biopharma company bears the
coordination risk. It is here that coordinating entities like QCTN Inc. and
new technologies such as collaborative electronic work environments and
portals can play a role in reducing the biopharma’s coordination risk and
reaping the benefits of accessing high-end, specialised groups.
Outsourcing Models
Over the last two decades, many biopharmaceutical companies introduced
outsourcing of preclinical and clinical studies and scale-up manufacturing
to CROs and CMOs as a way to create economy of scale and shorter time
to market. As CROs grew and became multinational companies in their
own right, the larger pharma companies entered into long-term, crossborder arrangements with such CROs in order to achieve the
aforementioned benefits and to try to reduce R&D costs. Typical
outsourcing models are the one-vendor model, the preferred vendor model
and the best-of-breed model.
In the one-vendor model, a CRO provides end-to-end R&D services
across (parts of) the R&D pipeline to a biopharma company. In this model,
the biopharma company deals with one CRO only. Very few CROs can claim
(and demonstrate) that they have available in-house, all services and all
required (medical) expertise. In the preferred vendor model, the contracted
CRO can provide many services but uses sub-contractors to complement
Translational Research and Bioinformatics in Queensland
Managers and scientists in medical research institutes, universities,
pharmaceutical and biotechnology companies, laboratory equipment
manufacturers and relevant software companies have witnessed an
explosive development in the application of high-end computing,
laboratory automation, computational biology, medical research and
molecular sciences. The convergence of these disciplines brings about a
fundamental paradigm shift in the way medical research, drug research
and, ultimately, patient care is undertaken. Hence translational medicine
is the continuum by which the biomedical community aims to move
research discoveries from the laboratory into clinical practice to diagnose
and treat patients.
Examples in this context are the emergence of disease-centered
visualisation of biological pathways, genetic profiling enabling
personalised medicine, and the ability to identify auto-antibody
“signatures”, i.e. profiles of potentially hundreds of biomarkers which are
In addition, new exciting R&D capabilities have emerged as a result of the
convergence of genetic research, bioinformatics and IT. As a result of these
developments, biopharmaceutical companies are reassessing their R&D
strategies as well as their R&D business models, i.e. the way they have
organised their R&D processes.
www.jforcs.com
JCS 73
indicative for a particular disease. According to a very recent report,
Australia could realise a net economic benefit of more than $12 billion
over five years by wider adoption of pharmacogenomics (PGx) which has
the clear potential to improve patient safety and quality of care by
reducing adverse drug events and improving the effectiveness of the
pharmaceuticals by prescribing the right dose the first time (5).
These promising directions depend heavily on the strategic use of
genomics, proteomics and metabolomics (“-omics”), but these techniques
produce a tremendous amount of data that has to be managed, analysed
and interpreted in a relevant biological and medical context. Clearly,
bioinformatics has become a critical capability. Bioinformatics is the
application of information technology, statistics and mathematics to
biological and medical problems involving large volumes of data with
complex interrelationships. It provides the foundation for much of modern
medicine and biotechnology and is evolving rapidly into a complex multidisciplinary field encompassing nearly all areas of biological, translational
and clinical research. Examples of how this is manifested can be found in
the article (elsewhere in this journal) by Baker and Gorse of the Queensland
Facility for Advanced Bioinformatics (QFAB).
The early recognition of the abovementioned developments by State
and Federal Governments and R&D service providers in Australia, and the
corresponding response in investment in infrastructure and attracting
world-class researchers, has made Australian institutions and service
providers future-ready in terms of their translational research and
bioinformatics capabilities. A recent example is the investment by the
Queensland and Australian Governments of AUD $300 million in a new
Translational Research Institute in Brisbane. Another example is Professor
Ian Frazer of the University of Queensland who discovered Gardasil. These
developments provide huge opportunities for international sponsors to
establish new collaborations with cutting-edge research facilities across all
areas of human disease research, drug and diagnostic discovery and
development, and bioinformatics in Australia. In this context, QCTN
facilitates international bio-pharmaceutical companies to visit Australia
and to explore the numerous opportunities for R&D and commercial
collaborations on offer.
QCTN will hold its first Translational Research Excellence symposium,
called TRX09, in Brisbane, Australia, in October 2009. This showcase will
provide an excellent opportunity for the global biopharma industry to see
what the Queensland-based translational research institutes and
commercial service providers have to offer. Immediately after TRX09, the
international biotechnology conference AusBiotech 2009 will be held in
Melbourne, 27-30 October 2009.
Clearly, QCTN’s mediated service provision now extends beyond the
traditional preclinical and clinical services to provide the biopharmaceutical
industry a very modern offering in terms of translational research
capabilities and a best-of-breed network of service providers (figure 1).
Figure 1:
QCTN: Network of Specialised R&D Service Providers
QCTN is a not-for-profit peak industry association (cluster) initially
established with funding from the Queensland Government and
representing national and international businesses (QCTN members) that
have a presence in Queensland, Australia – and which represent every
component in the therapeutic product development pipeline. QCTN
members are life sciences research organisations and commercial R&D
service providers and related entities serving the pharmaceutical,
biotechnology, complementary medicines and medical devices industries.
It is important to realise that QCTN is a coordinating body and does not
itself undertake any research activities.
McKinsey has partnered with the World Economic Forum to create an
“Innovation Heat Map,” by identifying factors that are common to
successful innovation hubs. As part of this effort, they have examined the
evolution of hundreds of such clusters around the world and analysed over
700 variables, including those driving innovation, and classified innovation
clusters into four categories. One category is called “Hot springs” which are
small, fast-growing innovation hubs on track to become world players.
QCTN is based in Brisbane and the McKinsey analysis identified Brisbane
as one of the few innovation “Hot Springs” (6).
QCTN has a business model which allows sponsors to outsource
elements of their preclinical research and clinical research to QCTN’s bestof-breed network of service providers, which gives sponsors more flexibility
and access to high-quality, customer-focused research and service delivery
(figure 2).
Figure 2:
To further support the local CRO industry and biopharma industry’s
legitimate desire to reduce “time-to-data”, QCTN has established an
independent Institutional Biosafety Committee (IBC) and an independent
Human Research Ethics Committee (HREC), the Australian equivalent of
an IRB, making use of Australia’s favourable regulatory regime for
undertaking preclinical and clinical research as explained elsewhere in this
journal. Working both of these committees in tandem further assists
sponsors in undertaking time- and cost-efficient clinical research in
Australia.
In this internet age, our collaborative and networked best-of-breed
model clearly has caught the attention of the international biopharma
industry, with American and Japanese companies leading the pack.
Network of Networks
Recognising that no single entity, regardless of their size and reach, can
now bring a new product to market, QCTN has established strategic
74 JCS
www.jforcs.com
partnerships with the Korea Health Industry Development Institute
(KHIDI) and the Gangwon Technopark (GWTP), both in South Korea, the
Kansai Bio Promotion Council (KBPC) of Japan, and BIOCOM, the peak
industry association representing the Southern Californian life sciences
industry.
These partnerships entail among other things the undertaking of
collaborative projects and programmes, introducing sponsors and service
providers and organising conferences and seminars. For sponsors this
means that the QCTN and its network of networks of academic and
commercial R&D service providers extends beyond the borders of Australia
and ensures that sponsors have the opportunity to work with global leaders
regardless of where they are located.
Conclusion
Biopharmaceutical companies are looking at new R&D business models
by compartmentalising, outsourcing and networking their R&D activities
with a multitude of research organisations. Given the explosive
development in the application of high-end computing, laboratory
automation and molecular science, QCTN has pulled together a cluster of
Australian R&D service providers with excellent and mutually
complementary capabilities in the fields of translational and clinical
research, supported by a robust bioinformatics and biostatistics
www.jforcs.com
infrastructure. QCTN’s role is to coordinate and facilitate between national
and international sponsors and its Members - Australian R&D service
providers.
Australia can serve as a safe stepping-stone to the Western Markets,
since data generated in clinical trials in Australia is generally well received
by the American and European regulators – in fact most of the early phase
trials done in Australia are for US and EU companies – to repatriate the
data for use in their regulatory jurisdictions. Several Japanese
pharmaceutical companies are also now undertaking preclinical and
clinical research activities in Australia, not only accessing specialised
expertise but also realising cost efficiencies and time benefits.
As Australia’s peak service industry representative organisation, QCTN
invites biopharmaceutical companies to discuss their product development
requirements in light of the state-of-the-art translational medical research
and bioinformatics capabilities and expertise amongst its member
organisations and associated networks. I
Otto Damsma. Prior to joining QCTN as business
development manager, Otto Damsma held the
positions of director of clinical data management
and biostatistics and director of information
management for a major international
pharmaceutical company.
Email: [email protected]
JCS 75
FACILITATING GENOMICS
AND TRANSLATIONAL
RESEARCH
As a result of the mapping of the human genome, along with recent
significant advances in technologies used to study genomes, genomic
research is now yielding increased amounts of information and
understanding about the role and function of genes in human disease.
Consequently, this increased understanding and level of information
relating to the human genome is now enabling scientists to translate this
information in such a way that this will lead to new diagnostic tests and
therapeutics. The impact of genomic research will likely lead to a shift in
the clinical management of human disease from treatment based on
symptoms to treatment based on each person's unique genetic make-up.
From the laboratory bench to the patient’s bedside, discoveries in genomic
science will increasingly lead to the translation of basic scientific discoveries
that will lead to clinical applications such as new genomic technologybased diagnostics and treatments.
In the context of the human genome, translational research is where
the data and tools necessary to identify genes are utilised so that there is
a better understanding of how genes play a role in diseases and the
genetic changes which contribute to disease progression and response to
therapy.
The Australian Genome Research Facility Ltd (AGRF).
Now in its twelfth year of operation, the AGRF operating model has
continued to evolve as genomics research has evolved. Landmark projects
such as the Human Genome Project have directly influenced the
remarkable advances in the efficiency, automation and throughput of
technology platforms for genomic research. The latest technology
platforms for genomic research are offered by AGRF via an integrated and
scalable genomic service pipeline (refer to Chart 1 below).
As a consequence, AGRF’s role as a genomics service provider is
www.jforcs.com
characterised by a core focus on enabling genomic research via access to
a suite of technology platforms, as well as collaborative rather than
transactional relationships with customers. Typically, this means AGRF
works with its customers from project planning, to data production, to
bioinformatics analysis.
The role of AGRF in supporting translational research
Access to a fully integrated service pipeline means that for genomic
researchers, the application of many of the rapidly evolving technologies
to real-life applications is now possible. An example of how current genome
research technologies are used is in the area of genome-wide association
studies (GWAS). Such studies enable the researcher to find and understand
the genetic contributors in diseases such as cancer (eg breast and colon
cancers).
The use of state of the art technologies along with computerised
databases means that GWAS of clinical samples for genetic variations and
their potential impact on disease is now rapid and accurate. As such, the
use of GWAS in a translational research setting has the potential to impact
on downstream patient care and disease management. In cancer research,
information generated by GWAS could lead to improved outcomes for
patients via a better understanding of the role of genetics in factors such
as disease predisposition, progression and response to therapy. I
Tony Feneziani is Sales and Marketing Manager at AGRF (Australian Genome
Research Facility Ltd ) with responsibility for sales, promotion and positioning of
AGRF's new and existing services to local and regional genomics markets in academia
and industry. Tony has a Science degree with honours in Biochemistry and prior to
joining AGRF he worked for 17 years in the life sciences and diagnostics markets with
Boehringer Mannheim and Roche Diagnostics.
JCS 77
FLEXIBLE FRAMEWORK
FOR DATA MANAGEMENT
AND BIOSTATISTICS
FUNCTIONS
Current Scenario
Several models such as Functional Outsourcing and Full Time Equivalent
(FTE) have evolved in Clinical Data Management and Biostatistics function
and been implemented by biotech and pharmaceutical companies. Each
of the models have their own advantages and shortcomings. These models
have been received well with large pharmaceutical companies who have
the resources / budgets to customize the service offerings provided by large
CROs. Mid and small sized pharmaceutical companies do not find it
comfortable working with large CROs on these models due to a variety of
reasons which include
•
•
•
•
•
Very high costs for Data Management activities
Lack of transparency in pricing structure
Need to re-negotiate prices with study changes
High Project Management costs
Quality issues with offshore teams
CDM and Biostatistics services for small / mid sized companies should focus
on accountability, cost-effectiveness as well as flexibility without
compromising on quality of deliverables.
LAXAI’s Unique Solution
To address the unique requirements, LAXAI provides its customers a framework to carry out Clinical Data Management and Biostatistics services. This
framework is based on a global delivery model from US and India and a
competitive unit pricing model for CDM services. The key benefits of this
model include
•
•
•
•
•
•
•
•
•
•
Risk sharing
Unit based pricing model (Pay only for units consumed)
Knowledge Sharing
Cost competitive
Transparent pricing model
Combination of offsite (NJ,USA) and offshore model (India)
Contingency staffing plan for quick ramp up / down
No infrastructure investments to make
LAXAI SOPs available for DM , Biostatistics, IT Support and
CDISC compliance
Open lines of communication with the client
The Unit Pricing model provides the customer with a clear understanding
of what to expect from LAXAI based on the itemized costing structure. The
Unit Pricing model has 2 parts, the first one is activity or task based billing
and the other one is milestone based billing.
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Tasks which fit under milestone billing include where the cost is fixed for
the deliverable and this does not change:
•
Data Management Plan
•
Statistical Analysis Plan
•
Database setup and Validation
Tasks which fit under activity / unit based and are driven by the units
consumed for a particular billing period. Some of the activities which can
be classified under this category include:
•
•
•
•
•
•
•
Edit Checks
Number of pages data entered
Number of queries raised to site
Number of AE Terms coded / Number of Conmed terms coded
Number of SAS datasets created
Number of Tables, Listings and Figures
Number of Status meetings attended by the team
LAXAI uses a blended outsourcing model where critical functions are
executed from its NJ, USA solution center and non-critical functions are
executed from its Hyderabad, India solution center. Program Management,
Project Management and Lead Data Manager/ Biostatisticians are from
the US. Technical activities such as Database Build, Edit Check
Programming, SAS Programming, double data entry are carried out from
India. This model ensures that the key management team is in constant
communication with the client and are accountable. Activities are shared
between offsite and offshore teams.
LAXAI Program Management team works closely with the client to identify
performance metrics for the partnership and ensure that they are collected,
reported and reviewed. Setting up a metrics program for the partnership
between CRO and the sponsor provides transparency, identifying areas of
improvement, taking corrective corrections as needed and provides a
quantitative measure of the performance of the partnership. The metrics
program emphasizes on reliability, predictability and cost reduction for
Data Management and Biostatistics functions.
Conclusion
The model suggested above requires the commitment from both the client
as well as the CRO to make it a success. Both the parties should foster a
long term relationship of trust and knowledge sharing. Return on
Investment should not be calculated in the short term and should look at
medium to long term considering both the tangible and intangible benefits
associated with the framework.
JCS 79
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Synergy Research Group is a Russian CRO, successfully operating in Russia
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