2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Altogether, there are large differences in the level of
evidence underlying the application of off-label use in patients
with advanced STS. It should be this evidence that
determines whether a certain drug should be given off-label
to a particular patient category. Some might argue that
physicians should be very cautious not to spoil the precious
time of patients suffering from diseases with a short and
dismal prognosis by exposing them to drugs with uncertain
efficacy and certain toxicity. Others might note that for some
patients, being denied a chance to benefit from uncertain
drugs, even with the certainty of toxicity, could be unacceptably
grim and could further affect negatively the patient’s
own perceived quality of life. There are many individualspecific
variables in these equations, and the lack of data
makes “evidence-based” decision making challenging if not
impossible.
Apart from some rare exceptions such as imatinib as
first-line treatment in advanced GISTs yielding unprecedented
outcomes, whether a new regimen outperforms best
supportive care in terms of OS and quality of life (the
ultimate goals we should strive for in our patients) can only
be determined in the context of adequately designed and
rigorously conducted randomized studies. Additionally, offlabel
use of drugs can be accompanied with issues of legal
responsibilities and costs. If there is a reason to treat a
patient with an off-label drug and it is ensured that an
individual patient can get access to the drug, a patient
should be informed about these potential consequences. Also
in health care systems where costs of drugs are covered by
society and not by an individual patient, such as in the
Netherlands, costs of off-label drugs, in particular expensive
ones, can be a major issue. In such situations, prescribing
off-label medications will eventually be at the expense of the
whole system and subsequently will have an effect on the
health care provided to other patients. But again, legislation
on off-label use greatly differs between countries.
For patients for whom no standard therapies are available
and who are candidates for further treatments, participation
in a clinical trial rather than off-label use should be the next
step. Many physicians are convinced that sorafenib is potentially
effective in patients with advanced GIST, yet no
randomized trials have been developed to test this agent,
which was already approved by the FDA in 2005. Clearly,
there are currently too many barriers to set up such studies.
At a global scale, patient advocacy groups, physicians, regulatory
agencies, health insurance companies, and politicians
should join forces to facilitate the efficient design,
development, and deployment of such clinical trials. In this
way, our field might determine more swiftly whether a
promising drug should be implemented as an accepted
standard in daily clinical practice. And if so, labeling of such
a drug should be adjusted, thereby taking away all potential
financial and legal burdens associated with the use of an
off-label drug.
The Role of Physicians in Advocating for Patients
When Cost-effectiveness Is Questioned by
Administrative Bodies Such as NICE
The Physician’s Duty as a Clinical Expert
Physicians in certain countries may be called on to participate
in the regulatory process by serving as clinical experts.
The role of such clinical experts varies depending on the
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regulatory setting: for example, the role of an expert physician
on the Oncology Drugs Advisory Committee (ODAC) in
the U.S. FDA process is significantly different from the role
of an expert physician advising a governmental regulatory
body such as the National Institute for Health and Clinical
Excellence (NICE) in the United Kingdom. With NICE, the
focus is often on evaluating the cost-effectiveness of a new
treatment, rather than the risk-benefit, which is often the
subject of other regulatory bodies such as the FDA or the
European Medicines Agency. The first thing to recognize
when accepting the task of clinical expert in relation to
determining the cost-effectiveness of a new treatment is that
such physicians have a similar duty to that of an expert
witness in court. In order to be credible, one needs to be
(1) well-briefed, (2) prepared for robust cross-examination,
(3) demonstrably independent of the pharmaceutical company
whose product is the subject of discussion, and (4) able
to argue effectively on behalf of the group of patients to
whom the treatment relates.
The United Kingdom’s NICE as an Example of a Societal Process
in Drug
NICE was set up to oversee the evaluation of new treatments.
Its deliberations and standard operating procedures
are being followed by other countries, which is why we chose
to scrutinize the way that it operates. One of the stated aims
of NICE was to reduce the inequalities of access to novel
therapies according to the geographical location of the patient
and the local financial arrangements. This was to be
done by providing a robust method of determining costeffectiveness,
and if a drug was deemed to be cost-effective,
it would be made available everywhere in the country. In
fact, within the United Kingdom this only applies to England
and Wales; Scotland has a different system called the
Scottish Medicines Consortium, which appears to have a
more streamlined approach and usually produces a decision
soon after licensing. Unfortunately, NICE has not succeeded
in abolishing the “postcode lottery” for a variety of reasons,
including not yet carrying out appraisals on certain drugs
for rare cancers, and because it has always been possible to
appeal to local funding bodies and more recently a regional
Cancer Drugs Fund, in order to try and circumvent a
negative NICE appraisal decision. Unfortunately, the application
of these mechanisms is inconsistent across the
country, hence the persistence of regional variations. Not
surprisingly, this gives rise to considerable distress among
patients. This pattern would most likely be applicable to
other countries trying to introduce a similar mechanism of
health care rationing.
The biggest source of controversy concerns the methods
used to generate data on cost-effectiveness. The process of
model generation is open to tender and groups of health
economists, generally based in academic institutions, bid for
the job of evaluating the new agent. The models used are not
placed in the public domain and hence cannot be directly
challenged, and it is openly acknowledged in certain technology
appraisal documents that many assumptions have
been made owing to the lack of data on quality of life,
survival of patients in disease subsets, etc. In some cases the
results produced by different models for the same drug in
different appraisals vary significantly.