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Over the last ten years,
getting patients and doctors into
clinical trials has become the
most delay-ridden aspect of the
drug discovery and
development process. When
implemented effectively,
clinical trial recruitment
(CTR) initiatives can be highly
successful. Time lines can be
dramatically reduced and
recruitment targets can be met
ahead of schedule; every day saved
in the progression to marketing
authorization can equate to
millions of pounds made in
patent-protected sales revenue.
However, great care is needed
in the development of a CTR
program. Considerable
ethical scrutiny is applied to
all patient recruitment materials
and initiatives. For example, in
2002 the European Commission
issued guidelines for consultation
which require patient
advertising and details of
recruitment initiatives to be
submitted to appropriate ethics
committees.
Unfortunately, there is no
simple code of practice
established and no unified
regulatory body and no recourse to
appeal. If an ethics committee
doesn't like what a CRO has
planned, the CRO can't use it. In
Europe, this aspect has yet to be
effectively addressed.
Enhancing CTR is obviously an
area in which great caution is
required. Some investigating
doctors, for example, question the
need for extra activities as, they
claim, there are sufficient
numbers of suitable patients among
those already attending their
clinics. However, practical
experience has shown that this is
an over-estimation of the number
of patients physicians will be
able to recruit and it is
estimated that only about 10% of a
physician’s patients will actually
wish to enroll in a
clinical trial.
Perhaps more importantly, there
are also objections raised from
within the industry. These usually
centre on a highly cautious
approach to the ethics and
legitimacy of patient-facing
initiatives. Some nervousness is
understandable given the strict
controls that govern DTC marketing
but for clinical research there is
a critical need for increased
patient understanding and
education. The signs are that the
caution of the industry is slowly
giving way to a new openness and
confidence.
A review of recent press
coverage also highlights a deep
skepticism of industry involvement
in clinical research. If not
approached ethically, a firm’s CTR
campaign can leave them wide open
to aggressive
media criticism and adverse
advocacy relationships. The key
point to remember is that the
objective of all this work is
ultimately to improve care for the
patient. A strenuous effort to
maintain this focus throughout
clinical development will
ultimately allow pharma companies
to reap considerable rewards.
Over the past several years
these problems have been addressed
in the US, where clinical research
receives more and more active
support of government bodies,
advocacy groups, charities and
patient groups. This provides a
collaborative environment and
ensures that there is always an
independent counterpoint when the
integrity of industry-sponsored
studies is attacked.
The American public sees a vast
amount of government-sponsored
education, designed to maximize
understanding of clinical trials.
A quick look at Cancer.gov and
ClinicalTrials.gov, both run by
the National Institutes for
Health, illustrates just how much
work is being done. This in turn
is supported by private efforts
such as Centerwatch.com, which is
currently offers a 300-page book
on informed consent for patients.
Healthcare provision
The nature of American
healthcare provision no doubt
motivates patients to seek free or
subsidized medication, but the
investment, approach and
partnerships in the US are
demystifying clinical trials and
generating considerable goodwill
toward industry-driven research.
US public/private partnership
A recently announced US
public/private partnership
designed to improve trial
recruitment demonstrates how
support for industry research can
be broadened. The initiative
created a $6m fund, which the
contributing pharma companies and
National Cancer Institute will use
to accelerate patient recruitment
for Phase I and II cancer studies.
Naturally, the credibility of the
public bodies involved enhances
the effectiveness of the scheme.
Study Designs and Methods
A common pitfall is
insufficiently rigorous evaluation
of study designs and methods. A
"straw poll" during a clinical
project management training course
revealed that virtually all
clinical protocols have at
least one amendment during the
study. The reasons appear to cover
the full range, from reliance on
well-established designs without
allowing newer, more creative
ideas to be considered and, at the
other extreme, not testing new
methods for the current
application. For example, in a
recent angina study, treadmill
exercise testing was used as the
primary efficacy criterion. This
is, of course, extremely
well-validated methodology, but,
in this case, the patients were
elderly, so the exercise protocol
was substantially modified to
reduce the physical demand. The
problem was that with such a mild
exercise protocol, less than half
the patients recruited showed
sufficient electrocardiogram (ECG)
changes to qualify for
randomization. A quick pilot
study would have alerted the
sponsors before committing to
major cost.
The Role of Senior Management
A recurring theme in clinical
research is the role of senior
management. By this we mean not
the head of clinical research, not
the head of R & D, but corporate
management. The costs and risks of
failure in the clinical phases are
so large that they should be
occupying much of top management's
attention. Yet, in many companies,
requirements, objectives, budgets,
and deadlines, are imposed without
any negotiation. On top of this,
major changes are commonly
dictated by
management, usually by
changing priorities. How can the
clinical project manager fulfill
top
management's aspirations,
with-in an increasingly
constrained environment?
Predicting the
Unpredictable-Managing Risk
All research and development
must involve some risk. Some of
the risks are typically
encountered in the main stages of
a typical clinical trial. The
values for risk level and lateness
are those usually applied in our
company when planning studies.
They useful rules of thumb.
Whatever rules are used, they will
almost certainly be better than no
risk assessment at all.
Risk Distribution in Clinical
Phases
Delivering the results on time,
to the required standard, may have
a lower risk in phase I than in
later phases, mainly because
subjects are healthy and not
potentially complicated patients,
and thus, recruitment can be
predicted with some confidence.
However, first administration to
humans is something of a leap into
the unknown, and safety problems
are always to be considered. What
is possibly less obvious is the
risk of any early-phase design
errors to later phases and to the
whole drug project. Once phase III
is imminent, perhaps there is a
degree of confidence emerging, as
much more is known about the drug.
The requirement for phase III,
therefore, may be seen as
accumulating data to enable a
product license application. In
fact, the great expansion of
activity dictated by phase III
studies introduces even more
complexity and a new set of risks.
The application of the drug to a
more realistic clinical setting
means that we will not necessarily
by studying "clean" patients.
Patients will often have other
diseases on top of that under
study and will only be under
observation for a small proportion
of the time. Attention to
clinical protocol design,
thus, is at least as critical as
in phases I-II.
Key Tasks and External
Agencies
The most common reason for late
tasks and projects is that they
started late. Before patients can
be screened for entry, a
well-established set of start-up
tasks must be completed, and of
these, some are relatively easy to
plan, and others are less
predictable. Those relying on
internal agreements (e.g., drug
supplies, protocol sign-off), can
be expedited by instilling the
right culture of negotiation
between departments and
individuals. But what of the
external elements, particularly
regulatory and ethics approvals?
The former is, fortunately,
reasonably easy to plan, because,
in most countries, there are clear
limits to the time and effort
required to meet the regulators'
requirements. Much more difficult
is the matter of ethics approval.
Across the European Union, ethics
committee practices vary
enormously, in USA, Canada, so
that, when planning a
multinational study, good local
knowledge is essential. Even
within the same country there is
little consistency, especially
since the demise of single central
approval for multicenter studies.
Theoretically, local research
ethics committees (IRB-s) are
expected to follow Department of
Health guidelines , but, if they
choose not to do so, there is
apparently no redress, so one may
be presented with unexpected
delays in particular centers
because of widely varying IRB-s
practices. There is a move towards
rationalization in n the form of a
two-level approval process. A
central committee will review the
study and, if approved, pass it on
to local committees for
ratification. In the U.S., the
Institutional Review Board
(IRB) has clearer responsibilities
and reporting lines . In
Australia, central approval is
still possible, and the ethics
committee sees itself as a more of
a partner in research rather than
a regulator, and very rapid study
start-up is possible. The message
here is that, if you do not have
compelling reasons to conduct your
studies in any particular country,
be creative with your planning,
and consider the big advantages
you might gain in another part of
the world. If you are forced to
live with the problems outlined
above, obtain the best and most
recent information you can from
the ECs / IRB-s and from their
users, and build this
realistically into your plans. The
plans might not look as good as
you would like, but you will have
a better chance of keeping to
them.
