Europe is a “second class continent” for cancer research

In
the 2 April 2005 issue, Rory Watson (page 746) discusses which funds are
available to support cancer research in the European Union (EU) as compared to
the United States (US). In absolute terms, US per capita spending is seven
times that in the EU. When these figures are normalised to gross domestic
product, this corresponds to a four-fold difference between the US and the EU.

Our
Rapid Response addresses the problem of how off-label prescriptions of
cytotoxic agents are managed in Italy.  In
particular, our intention is to show that, in our National Health System (NHS),
the funds for anti-cancer drugs are directed not only to cover the standard
therapeutic needs of cancer patients (i.e. financing labelled prescriptions),
but also to support research on innovative agents when they are tested for new
clinical indications (i.e. financing a certain proportion of off-label
prescriptions of anti-cancer drugs). Unfortunately, the public origin of  the funds for this latter form of research
is unrecognised by our governmental control organisms (see below). So, any
estimates of how many funds are directed in Italy to research on anti-cancer
agents seem to be unreliable or, at best, grossly underestimated. 

Our Rapid Response examines the background
and the economic implications of this problem (Point A), proposes one
hypothesis for reducing the drug expenditure of our National Health System in
this area (Point B), and finally contrasts the conclusion by Watson that
“Europe is a second-class continent in terms of cancer research funding” (Point
C).

Point
A: Background and economic implications.

In
the EU, the off-label prescription of cytotoxic agents is a controversial issue
in both in-patients and out-patients. Some off-label uses of cytotoxic drugs
are well-established and are supported by a strong therapeutic evidence (Case
1); the reason why these uses still lack regulatory approval is related either
to the very recent conduction of the relevant clinical trials or to the fact
that these drugs are very old (so that their manufacturer has no longer any
interest in updating their regulatory status).

Other
off-label uses of cytotoxic agents are not supported by any convincing
therapeutic evidence (Case 2); under these circumstances, the lack of
regulatory approval simply reflects the poor level of therapeutic evidence.

In
oncology, it is generally thought that off-label uses should be encouraged in
Case 1 and discouraged in Case 2.

Case
1 poses a series of economic implications and practical problems. In this Rapid
Response we consider the main points of controversy that can arise for the
in-patient prescription of these off-label drugs. In contrast, the case of
out-patient prescriptions is not dealt with.

The cost of the off-label prescription for oncological in-patients is
very substantial. Some surveys suggest that 
22% of the overall prescription in oncology is related to off-label uses
(Poole and Dooley, 2004). In other experiences, these figures prove to be
somewhat higher (Braud and Downs 2005; Kocs and Fendrick, 2003). For example,
our university hospital (Azienda Careggi, Firenze, Italy, 1900 beds) has a
yearly expenditure of  10,3 million
Euros for cytotoxic agents (year 2004); only at our hospital, one fourth of
this amount would yield a very impressive economic figure. In Italy, the
national figure of the yearly expenditure for cytotoxic agents has a magnitude
of around 900 million Euros (year = 2004; sum of in-patients and out-patients
prescriptions; source of this information: Osservatorio Nazionale sui Farmaci,
Report on national 2004 expenditure,  22
March 2005). One fourth of this amount would yield more than 200 million Euros
per year.

At
present, all off-label oncological uses in Italian hospitals are paid for by
our NHS (Scenario A: paying 100%). On the other hand, one could argue that this
type of therapeutic intervention might instead fall in the area of sponsored
clinical research; hence drug manufacturers, in this framework, should make at
least the experimental cytotoxic agents available at no cost to our patients
(hence, with no economic participation by our NHS; Scenario B: paying nothing).

Scenario
A has a drawback in that our NHS has to pay entirely for the off-label
prescription but has an important advantage in that patients are hopefully
treated at best. Scenario B minimises the expenditure for our NHS, but drug
manufacturers are very unlikely to fund, in whole or in part, these off-label
oncological prescriptions (e.g. by converting these uses from their present status
into the context of original clinical research). So, Scenario B might result to
be harmful for the patients.

Point
B: Hypothesis for reducing the expenditure for anti-cancer agents in the
Italian National Health System.

While
there is clearly no easy solution to this difficult problem, one strategy that
has been attempted at our hospital in 
Firenze is to document, for individual anti-cancer agents, which part of
their prescription is labelled and which part is off-label. Unfortunately,
collecting this information individually from oncological in-patients is not
straightforward (mainly because all Italian hospital pharmacies lack unit-dose
distribution systems). However, if this task is fulfilled through an ad hoc
manual work, one strategy to make decisions on individual off-label uses could
be based on the following three phases:

• Phase 1:  Reviewing the clinical evidence in
  support of the off-label use under examination. This allows to make the
  decision of either discouraging this off-label use (when the evidence is
  poor –Case 2-) or to maintain it (when there is a good evidence –Case 1-).
  
• Phase 2:  In situations denoted as Case 1,
  negotiating with drug manufactures how the economic burden of the
  off-label use can be distributed between public funds and drug
  manufacturers themselves. In these negotiations, one extreme is that the
  NHS pays 100% while the other extreme is that the NHS pays nothing (and
  the drug manufacturer pays 100%). Using appropriate negotiations, a
  compromise between these two extremes can be sought in order to: a)
  maintain the levels of therapeutic assistance to the patients; b) reduce
  the drug costs for  our NHS, c)
  transfer part of the off-label expenditure from public funds to drug
  manufacturers; d) construct original therapeutic information in terms of
  drug-efficacy studies conducted in in-patients (so that the additional
  expenditures incurred by drug manufacturers are partially offset by the
  original clinical research conducted on their drugs).
• Phase 3: forming an
  organism of our National Health System that is assigned the responsibility
  for a regular assessment of all off-labels uses in oncology. This organism
  could periodically issue a positive list of “appropriate” off-label uses
  (covering only in-hospital prescriptions). It is implicit that all uses
  not reported in the positive list are assumed to be inappropriate.

Point C: “Is Europe a second-class continent
in terms of cancer research funding?”

In Italy, our NHS is unaware that off-label prescriptions of anti-cancer
drugs represent an atypical form of experimental clinical research. Money spent
by our NHS on these off-labels uses (not quantified so far by any specific
survey)  should be considered, at least
in part, a direct support to cancer research. Hence, cancer research in Italy
might actually receive much more money than that estimated by analyses that
ignore the presence of off-label uses.

In summary, Watson has concluded that Europe is a second-class continent
because an insufficient amount of money is directed to research on anti-cancer
agents. Our arguments emphasise that, at least in Italy,  a substantial proportion of off-label uses
of anti-cancer drugs (and possibly also the research on these agents) is
actually funded by our National Health System using the DRG reimbursement method.
Since this method  does not
differentiate between labelled and off-label uses of these drugs,  any analysis that quantifies how much money
in Italy is devoted to research on anti-cancer drugs might underestimate the
real figures of this expenditure.

In Italy, our regulatory context allows to issue a positive list of
accepted in-hospital off-label uses without the need to change any existent
law. In contrast, extending this approach to out-patient prescriptions has more
profound reimbursement implications because this would require to change our
present laws on this subject.

REFERENCES

-     Braud E, Downs CG.Use of off-label
drugs in cancer care again under review.

ONS News. 2005 Mar;20(3):8

-    
Kocs D,
Fendrick AM. Effect
of off-label use of oncology drugs on pharmaceutical costs: the rituximab
experience. Am J Manag Care. 2003 May;9(5):393-400.

-          Poole SG, Dooley MJ.   Off-label prescribing in oncology. Support Care Cancer. 2004 May;12(5):302-5. 

ACKNOWLEDGEMENTS

We thank Dr.Enrico Tendi (Director of the Hospital Pharmacy of the
Careggi Hospital), Dr.Enrico Desideri (former General Health-Care Director, of
the Careggi Hospital), and Dr. Francesco Di Costanzo (Head, Medical Oncology
Clinics, Careggi Hospital) for their contribution to the development of the
monitoring project mentioned in this Rapid Response.