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Rapid response to:

Analysis
# NICE and the challenge of cancer drugs

BMJ
2009;
338
doi: https://doi.org/10.1136/bmj.b67
(Published 13 January 2009)
Cite this as: BMJ 2009;338:b67

## Rapid Response:

## Economic consequences of approval extensions: the case of rituximab

patients has raised

well-known issues of economic sustainability [1]. The majority of

comments in this area have focused

on new chemical entities, and particularly on new high-cost agents such as

monoclonal antibodies [1,2]. However, one problem that has so far attracted

little attention is the economic impact that can result from approval extensions (i.e. in situations where a

target

treatment, originally approved for its first clinical indication, receives

approval for additional indications, especially when large series of patients are involved by the approval

extension).

The case of rituximab is emblematic. The first approval of this agent

dates back to 1999.

After these initial approvals as induction therapy for some types of

non-Hodgkin's lymphoma (NHL) as well as for rheumatoid

arthritis, the drug has received in the past year the approval extension

also

for the maintenance treatment of NHL and

for first-line or second-line treatment of

chronic lymphocytic leukaemia (CLL).

What economic

impact can be predicted for the approval extension regarding CLL? A combined

analysis of epidemiological studies and administrative databases (Messori et al, unpublished observations,

2011) indicates that, in Italy, the

number of patients with CLL that will be treated with rituximab is

likely to be

around 2,000 per year. The cost

of this

treatment at standard dosages (500 mg/sqm for 6 cycles) is around EUR 14,000

per patient. This gives rise to a nationwide cost for the Italian health

care

system of EUR 28million per year.

If one carries out the same analysis considering the approval extension

for maintenance

treatment of NHL, the typical cost per

patient is around EUR 10,000 (at the dosage of 375 mg/sqm every

two months), while the total number of expected cases in Italy is around

1,500 per year (Messori et al. unpublished

observations, 2011). This translates into a total nationwide yearly

expenditure

for this new indication of EUR 15 milllion per year.

Figure 1 (that can also be seen from url www.osservatorioinnovazione.org/netma/rituximabfigure

.pdf)

shows the curve of predicted expenditure versus time for rituximab based

on a separate

analysis of these two new indications. The attainment of the maximum

number of patients has been modeled

as a gradual process. The equations governing this progressive attainment of

steady state are described in Appendix 1.

Overall, our data

indicate that, while the historical expenditure of rituximab in Italy has

been around EUR 140 million per

year, the approval of these two new indications

could imply an extra-budget of nearly EUR 45 million per year.

The price of rituximab has already been negotiated at the time of its

initial approvals (induction

treatment in NHL and rheumatoid arthritis), and so it is very unlikely that

this price can be renegotiated. Hence, the Italian agency will have very

limited opportunities to find a solution to appropriately govern the

economic

implications of this problem.

In conclusion, this example shows that, from the viewpoint of

expenditure predictions,

approval extensions can be, in economic terms, as relevant as approvals

of new

chemical entities. On the other hand renegotiating

the drug's price for approval extensions can be, in operative

terms, more difficult than the initial negotiation of firstly approved

indications.

References

1. Claxton K, Briggs A, Buxton MJ, Culyer AJ, McCabe C, Walker

S, Sculpher MJ. Value based pricing for NHS drugs: an opportunity not

to be missed? BMJ 2008;336:251-254 doi:10.1136/bmj.39434.500185.25

2. Raftery J. NICE and the challenge of cancer drugs.BMJ 2009

338:b67; doi:10.1136/bmj.b67

3. Gibaldi M, Perrier B. Pharmacokinetics. New York: Dekker, 1982;p.494.

4. Russo P, Mennini FS, Siviero PD, Rasi G. Time to market and

patient access to new oncology products in Italy: a multistep pathway

from European context to regional health care providers. Ann Oncol. 2010

Oct; 21(10):2081-7. Epub 2010 Mar 24.

5. Engelberg AB, Kesselheim AS, Avorn J. Balancing innovation,

access, and profits -- market exclusivity for biologics. N Engl J Med

2009;361:1917-1919[Erratum, N Engl J Med 2010;362:664.]

APPENDIX 1.The predictions in terms of yearly

expenditure illustrated in Figure 1 are based on a specific modeling

(see Box 1

for symbols and abbreviations) in which the mathematic equations employed to

generate the curves are the following:

Equation 1:

PATIENTS =

TARGET x (1 - e

^{-0.693/HLgrowth x TIME})for cases

where

the value of time was between 0 and LEdrug.

Equation 2:

PATIENTS =

TARGET x e

^{-0.693/HLobsolescence x (TIME - LEdrug)}for cases

where

the value of time was between LEdrug and infinity.

These curves were directly derived from

standard exponential equations that are identical to those commonly used for

pharmacokinetic modeling [3]. In the graphs, the starting point for the

curve

was set at a date equal to TIME0+LAGTIME and the curves were plotted

accordingly. In our analysis, LEdrug was set at 90 mos, HLgrowth at 3 mos,

HLobsolescence at 18 mos. The value of LAGTIME was set at 12 mos by assuming

that time zero was the approval by EMA [4].

The information on HLobsolescence

available

from the literature is very limited (e.g. see reference 5); furthermore, the

lack of adequate information affects not only HLobsolescence but also on

LEdrug, which are two strictly interrelated parameters influencing the

time-course of the "right tail" of the curves. For this reason, the model

reliability was thought to be insufficient for predictions extending

beyond the

achievement of a steady state; as a

result the curve represented in Figure 1 (large panel) was truncated at

the end

of 2015.

Box1. Parameters employed in the budget impact predictions described in

Appendix 1.

Parameter

ExplanationUnitsTARGET

Yearly population (at steady state) of

patients who are candidates to the new treatment

No. of patients

HLgrowth

Rate at which the number of patients

grows from 0 to TARGET; the process is assumed to be based on a

first-order

constant defined as 0.693/HLgrowth. Like in standard pharmacokinetic

calculations, the steady state is assumed to be reached after as much

time

has elapsed as five times the value of HLgrowth

Months.

LEdrug

Life expectancy of the drug (starting

from its marketing authorization until the beginning of its obsolescence

process)

Months

HLobsolescence

Rate at which the number of patients at

the end of LEdrug starts to decline from TARGET to zero; the process

of this

decline is assumed to be based on a first-order constant defined as

0.693/HLobsolescence. Like in standard pharmacokinetic calculations,

a value around

zero patients is assumed to be reached when as much time has elapsed

as five

times the value of HLobsolescence.

Months

TIME0

This parameter is defined as the

date of approval by the regulatory

agency.

Date (dd/mm/yyyy)

LAGTIME

Interval between TIME0 and the

time-point

where the curve of the expenditure starts; in practice, LAGTIME

expresses the

delay between TIME0 and the real availability of the product in the

market so

that this interval essentially includes the price determination (in

countries where

this negotiation takes place) and the inclusion in local

formularies.

Months

Competing interests:No competing interests26 May 2011