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International Clinical Trials
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To be successful in developing new cancer therapies, sponsors and CROs
need access to trained and invested investigators who have the skills
and sufficient resources to offer clinical trials to patients. Without a
motivated site, the process of enrolling patients into trials becomes
much more challenging. Sites may view CROs as service providers who are
unconcerned about the outcome of a clinical trial; therefore, CROs need
to better identify the site needs and approaches that strengthen
investigative site relationships in order to increase levels of ‘buy-in’
focused on achieving common goals.
Deployment of shared
technology to identify patient pools at hospital institutions is one of a
number of approaches that is explored here; in addition, research is
conducted to understand how CROs can creatively attend to site needs,
and how that can ultimately provide patients with the chance to access
potentially better cancer treatments.
Ongoing Pressure
There
are more ongoing clinical trials in the oncology area than any other
(see full PDF). While this is a positive reflection of the commercial
and not-for-profit institutional investment in cancer research, it
places enormous pressure on investigational sites in terms of their own
investment of time and resources.
The global spend in oncology
drug development is estimated to be $9-12 billion, with up to 40%
anticipated to be outsourced to CROs. Therefore, the CRO industry shares
a significant part of the pressure to successfully recruit patients to
clinical trials.
With quoted figures suggesting that less than
5% (US) and 17% (UK) of cancer patients have access to clinical trials
(1) – which admittedly, are subject to validation and scrutiny – it is
clear that in spite of the relatively high quantity of cancer therapies
undergoing clinical trials, the numbers of involved patients and, by
inference, sites, is unhelpfully small.
With the advent of
immuno-oncology and an explosion of basket or umbrella design studies –
where multiple combinations of immune-checkpoint inhibitors such as
PD-1, PDL-1, CTLA4, OX-40 antibodies and so forth are candidate
therapies across multiple tumour indications – the reality of many
clinical trials ‘cannibalising’ the same patient populations from a
seemingly unnecessarily restricted patient pool brings the problem into
sharp relief.
Fundamentally, it is the investigational site that
is the gateway to successful drug development. To this end, it is
necessary to fully understand the drivers for, and inhibitors to,
investigational site participation in the clinical trials that give
access to potentially beneficial novel cancer therapies to patients.
Indeed, the apparent paucity of involvement is a serious rate-limiting
step to the development process, as well as a significant driver of the
upward pressure on development costs. In a world where companies face a
demand to reduce costs, this is a toxic situation that needs addressing.
Research Process
ICON is undertaking a study to
better comprehend the key motivators and discouragements at site level.
Understanding these components is fundamental to establishing stronger,
better site relationships, which are less transactional and more
mutually beneficial and collaborative relationships.
The
structure of the study is to take an international sample of sites that
already participate in clinical trials – recognising that the sample is
skewed from the outset. However, with carefully directed inquiry, it
will be possible to extrapolate learning to encourage new sites into the
clinical development space.
Both principal investigators and
study site coordinators will be targeted in this web-based survey. It is
recognised that contributory facets are many and varied, but the key
areas are scientific, structural, financial and cultural.
Scientific
There
are pressures to answer as many scientific and clinical questions in as
small a number of studies as possible; however, this urgency can be
counterproductive. A reduction in the number of large, expensive
registration studies (1,000 patients or more) may be expected, but
instead, there is an emergence of larger proof of concept studies (up to
500 patients) – particularly as breakthrough drug designation/adaptive
licensing status is increasingly sought via the FDA and EMA
respectively.
These Phase 2 studies may well be basket and
umbrella designs or other novel adaptive clinical trial designs, but
these higher complexity protocols may be counterintuitive to mass
cooperation at sites. The more complicated the protocol, the greater the
chance that it is difficult to understand and comply with, leading to
more interventional techniques being applied in the pursuit of
biomarkers and resulting in a greater burden on both patients and
research teams. This research wishes to test this hypothesis directly
with sites.
Structural
In countries such as the UK,
the National Institute for Health Research – as part of the NHS –
provides for and encourages some protected research time for doctors.
Where the healthcare system is not nationalised, doctors may have more
choices to make as to how they spend their time, and may be encouraged
to research with support from the likes of the National Cancer Institute
in the US, for example. Other countries, like the Republic of Ireland,
may not have any research-protected time at all, so the possibilities to
participate in clinical trials can be structurally compromised.
In
addition, access to dedicated research teams – from research nurses,
study coordinators and data managers to physical space or equipment –
varies from institution to institution across countries. Financial
structures may also influence clinical trial participation. This
research will explore this structural aspect.
Financial
Funding
of clinical trials at sites is immensely complex. Hospital management
boards retain the highest level of involvement in negotiating financial
contacts to perform clinical trials in health establishments. Indeed,
contract negotiations are increasingly becoming the greatest
rate-limiting step in setting up trials in many countries across the
globe. From a sample of nine recent studies across 2,654 sites in 44
countries, it was found that contract negotiation and execution
accounted for 63% of the median cycle time for study start-up (2). How
the money from commercial, clinically sponsored trials is distributed
across departments and research staff is diverse, and research funding
from national research institutions can be opaque.
Furthermore,
in countries such as the US, the insurance reimbursement system can act
as a negative incentive for patients and doctors to participate in
experimental drug trials. After science, ethics and professional
curiosity, remuneration should be a key motivator in clinical trial
participation, and yet the processes for agreeing amounts and for
apportioning resources could delay, demotivate and disincentivise
stakeholders. Thus, further investigation is required.
Cultural
Thinking
about the cultural elements of clinical trial participation beyond
varying attitudes to clinical research between different countries,
institutional variances also need to be addressed. The polarised
outlooks between academic and community-based hospitals have already
been observed; what also needs to be considered is: how important is
research to career development in any particular medical community?
One
can hypothesise that where research publication is pivotal to career
progress, clinical trials will have a greater uptake by medical staff;
however, not all research is centred on Phase 1 through Phase 3 clinical
development, so it is not necessarily a direct correlate.
Another
key aspect of culture is the relative relationship between
collaborative academic research groups such as the European Organisation
for Research and Treatment of Cancer, NRG Oncology and BIG, and the
commercial biotechnology/ pharma industry and CROs. Attitudes towards
all of these stakeholders influence motivational elements for the
investigating physician team.
CRO Role
Arguably,
the cultural aspect of site motivation is the one that CROs can
influence greatly, particularly with a view to the improvement of site
relationships. How CROs interface with all the key players is likely to
make a significant difference to hospital research teams in the attempt
to make running increasingly complex clinical trials easier. CROs also
frequently act as a significant scientific champion for studies.
CROs
are also at the forefront of patient-centric monitoring (PCM). PCM is
growing in popularity and will be endorsed in revised EU Clinical
Regulations, which come into effect in November 2016. Such approaches
will make life simpler for sites in many ways and refocus site
interactions away from the obsessive and, arguably, overly narrow source
data verification to a more customised approach, assisting sites in
yielding quality data. CROs are also spearheading electronic training
platforms such as Firecrest® that make study information both more
visually and intellectually compelling, and more accessible to the whole
research team. Firecrest is also a platform for eConsent, which is
aimed at simplifying an essential but sometimes fraught procedure for
sites and patients alike, in a world where multiple consent forms for a
single study are becoming more common.
Given the increasing move
towards outsourcing commercial clinical trials, it can be argued that
CROs should have a much greater part to play. Influencing the many
additional factors that drive willingness to contribute to clinical
trials is an increasingly necessary skillset that CROs are expected to
provide as part of clinical trial execution. Reducing protocol
complexity, shaping research infrastructure and financial engineering
are all plausible if the greatest priorities of hospital oncology
researchers and their patients are truly understood.
Future Prospects
This
survey-based research into site relationships seeks to address
priorities in order to build a holistic picture on how to best support
the ever-greater pressures on oncology clinical development. Ultimately,
the resulting understanding of this space will help underpin the
success of the pharma industry, scientific advancement and, most
importantly, the future prospects of cancer patients.
References
1. National Cancer Research Institute – UK, 2013
2. Visit: www.iconplc.com/news-events/news/icon-reports-secondquart- 4/index.xml
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White Papers |
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Clinical Trials in Emerging Markets: Goldmines or Landmines?
Pharm-Olam, LLC
Over the past decade, biopharmaceutical companies
have increasingly turned to emerging markets as a way
to reduce clinical trial costs and timelines. Areas such
as Eastern Europe, India, and Latin America—with their
ready population of treatment naïve patients—can be an
answer to the intense competition for patients seen in
developed markets. Many of the countries within these
regions may now be considered as “emerged” countries
but yet, conducting trials in these regions does require
some special attention and expertise. Before deciding to
conduct studies in these areas, companies should have a
full appreciation for the ethical, medical, regulatory, legal,
and operational hurdles that must be surmounted for
success. Here we highlight a number of those issues and
offer our recommendations for how sponsor companies
can deal with them effectively.
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