Michael Rawlins criticism of the drug industry for profiteering is
not without basis as recently demonstrated by the long-running Lucentis
saga.
The National Institute for Health and Clinical Excellence this week
announced it would sanction the use of Lucentis (ranibizumab) for patients
with age-related macular degeneration (AMD).(1) This signals a u-turn from
its initial draft guidance that had originally concluded it would only be
cost effective compared with standard treatment if treatment was limited
for the better seeing eye only.(2) This implied only treating one eye and
therefore risk losing functional vision, which both doctors and patient
groups unsurprisingly found unacceptable. Both NICE and PCTs found
themselves pummelled by the media, ministers and patient groups, as well
as court action. The real issue that has not been addressed however is the
exorbitant price that the pharmaceutical company is able to charge the NHS
for a product that desperate patients are prepared to pay for.
Age-related Macular Degeneration (AMD) is the commonest cause of
visual impairment in the UK with around 26,000 new cases of wet AMD
annually. It is characterized by choroidal neovascularisation, an abnormal
growth of new blood vessels beneath the retina, which leads to loss of
central vision. In the last few years, new treatment modalities have been
developed for what was previously an untreatable condition. Lucentis and
Avastin (bevacizumab) are both recombinant human monoclonal antibodies
that work by binding and inhibiting vascular endothelial growth factor
which is the cause of choroidal neovascularisation. Avastin is a
glycosylated antibody whereas Lucentis is an antibody fragment although
the active component differs by only 6 amino acids. Avastin is licensed
for the treatment of metastatic colorectal and breast cancer, but not
intra-ocular use. Lucentis, on the other hand, is licensed for intra-
ocular use.
Lucentis is extremely expensive and there are significant cost
implications of widespread use. Drug costs per injection are of the order
of around £100 for Avastin but could be as low as £6 plus the cost of
aseptic preparation compared to £761 for Lucentis. For a 14 injection
course, this equates to roughly £1,400 for Avastin compared to £10,654 for
Lucentis.(3) For the typical Primary Care Trust (PCT) serving a population
of 250,000, it could expect around 107 new cases of wet AMD a year. The
cost of Lucentis treatment for these patients would amount to over £1.1
million per annum. Overall costs including outpatient review over 10 years
could add up to 1% of the total current NHS budget.
NICE estimated that Lucentis would cost between £17,800 to £35,200
per QALY gained depending on the type of wet AMD treated.(2) These costs
were estimated on the presumption that treatment is stopped after 2 years.
However, it is not known if the 14 injections course represents the
optimal dosing regimen and patients may require long term treatment and
follow up over many years. Lucentis was deemed to only be cost effective
for the NHS with a dose capping arrangement that reportedly has just been
agreed by the manufacturer.
Is there a case for Avastin? Although unlicensed for ocular use in
the UK, it is an internationally recognized treatment modality for AMD and
has been widely used off-label in thousands of patients worldwide.(4,5) As
Avastin and Lucentis are closely related, clinical efficacy and side-
effect profiles are likely to be similar. Several studies published have
so far suggested that Avastin is an effective treatment.(4,6,7,8) At
present, multiple case series have reported no short-term safety concerns
although the follow-up period may not be long enough to draw any firm
conclusions. One survey of 70 centres using Avastin worldwide, covering
7,113 injections in 5,228 patients, reported low adverse event rates of
less than 0.21%.4 It is also postulated that as Avastin is a larger
molecule, it may remain in the eye longer than Lucentis and therefore
allow for less frequent injections. On the other hand. manufacturing
standards do differ: for intra-ocular formulations, particulate matter has
to be very low and Avastin is not manufactured with that in mind.
From a cost point of view, Lucentis could be over 30 times more
expensive than Avastin. One health technology assessment published last
year concluded that due to the price differentials, Avastin would be more
cost effective even if there were differences in effectiveness and side-
effects.(9) This view is supported by cost effectiveness modelling which
showed that Lucentis would need to be 2.5 times more effective than
Avastin in terms of visual acuity.(10) The modelling estimated that the
annual cost to the NHS for treating 25,000 new cases of AMD annually would
be £300 million for Lucentis compared to £8 million for Avastin.
NICE unfortunately is unable to consider Avastin as it can only
assess drugs for their licensed purpose. The question then is why Avastin
has not got a license for intra-ocular use in the UK. Genentech, the
company that manufactures both Avastin and Lucentis has been reluctant to
apply for a license for Avastin for AMD. This is perhaps unsurprising as
it is in a position of imperfect agency and stands to make considerable
financial gains from Lucentis.
Health commissioners face a dilemma between choosing Lucentis, where
there is reasonably good evidence for clinical effectiveness and safety
but with a high cost, versus Avastin which is considerably cheaper and
more affordable but lacking in enough evidence to support its use. The new
NICE position obliges local commissioners to use Lucentis, and will no
doubt be trumpeted by patient groups as a victory for patients. However,
it is a hollow victory as cash-strapped Primary Care Trusts, often
“villainized” by the media for their Scrooge-like tendencies, will now be
under more pressure than before to find resources with which to fund this
costly treatment. The redistribution of resources invariably could imply
other services suffering as a consequence. Where some patients gain,
others will no doubt lose out. The only real winners are the makers of
Lucentis.
References
1. National Institute for Health and Clinical Excellence (2008).
Press release : 2008/052 NICE issues final guidance on the use of
ranibizumab and pegaptanib for the treatment of age-related macular
degeneration (AMD). London: NICE.
2. National Institute for Health and Clinical Excellence (2008).
Macular degeneration (age-related) – pegaptanib and ranibizumab: Appraisal
consultation. London: NICE.
3. Drugs and Therapeutics Bulletin. A view on new drugs for macular
degeneration. Drugs and Therapeutics Bulletin 2007; 45 (7):49-52.
4. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal
Bevacizumab Safety Survey: using the internet to assess drug safety
worldwide. Br J Ophthalmol 2006; 90:1344-1349.
5. International Council of Ophthalmology International Clinical
Guidelines. Age-related Macular Degeneration (Management Recommendations).
April 2007 http://www.icoph.org/guide (Accessed 4/4/08)
6. Spaide RF et al. Intravitreal bevacizumab treatment of choroidal
neovascularization secondary to age-related macular degeneration. Retina.
2006 Apr; 26(4):383-90.
7. Maturi RK et al. Electrophysiologic findings after intravitreal
bevacizumab (Avastin) treatment. Retina. 2006 Mar; 26(3):270-4.
Rapid Response:
The Lucentis Saga: NHS 0 Pharma 1
Michael Rawlins criticism of the drug industry for profiteering is
not without basis as recently demonstrated by the long-running Lucentis
saga.
The National Institute for Health and Clinical Excellence this week
announced it would sanction the use of Lucentis (ranibizumab) for patients
with age-related macular degeneration (AMD).(1) This signals a u-turn from
its initial draft guidance that had originally concluded it would only be
cost effective compared with standard treatment if treatment was limited
for the better seeing eye only.(2) This implied only treating one eye and
therefore risk losing functional vision, which both doctors and patient
groups unsurprisingly found unacceptable. Both NICE and PCTs found
themselves pummelled by the media, ministers and patient groups, as well
as court action. The real issue that has not been addressed however is the
exorbitant price that the pharmaceutical company is able to charge the NHS
for a product that desperate patients are prepared to pay for.
Age-related Macular Degeneration (AMD) is the commonest cause of
visual impairment in the UK with around 26,000 new cases of wet AMD
annually. It is characterized by choroidal neovascularisation, an abnormal
growth of new blood vessels beneath the retina, which leads to loss of
central vision. In the last few years, new treatment modalities have been
developed for what was previously an untreatable condition. Lucentis and
Avastin (bevacizumab) are both recombinant human monoclonal antibodies
that work by binding and inhibiting vascular endothelial growth factor
which is the cause of choroidal neovascularisation. Avastin is a
glycosylated antibody whereas Lucentis is an antibody fragment although
the active component differs by only 6 amino acids. Avastin is licensed
for the treatment of metastatic colorectal and breast cancer, but not
intra-ocular use. Lucentis, on the other hand, is licensed for intra-
ocular use.
Lucentis is extremely expensive and there are significant cost
implications of widespread use. Drug costs per injection are of the order
of around £100 for Avastin but could be as low as £6 plus the cost of
aseptic preparation compared to £761 for Lucentis. For a 14 injection
course, this equates to roughly £1,400 for Avastin compared to £10,654 for
Lucentis.(3) For the typical Primary Care Trust (PCT) serving a population
of 250,000, it could expect around 107 new cases of wet AMD a year. The
cost of Lucentis treatment for these patients would amount to over £1.1
million per annum. Overall costs including outpatient review over 10 years
could add up to 1% of the total current NHS budget.
NICE estimated that Lucentis would cost between £17,800 to £35,200
per QALY gained depending on the type of wet AMD treated.(2) These costs
were estimated on the presumption that treatment is stopped after 2 years.
However, it is not known if the 14 injections course represents the
optimal dosing regimen and patients may require long term treatment and
follow up over many years. Lucentis was deemed to only be cost effective
for the NHS with a dose capping arrangement that reportedly has just been
agreed by the manufacturer.
Is there a case for Avastin? Although unlicensed for ocular use in
the UK, it is an internationally recognized treatment modality for AMD and
has been widely used off-label in thousands of patients worldwide.(4,5) As
Avastin and Lucentis are closely related, clinical efficacy and side-
effect profiles are likely to be similar. Several studies published have
so far suggested that Avastin is an effective treatment.(4,6,7,8) At
present, multiple case series have reported no short-term safety concerns
although the follow-up period may not be long enough to draw any firm
conclusions. One survey of 70 centres using Avastin worldwide, covering
7,113 injections in 5,228 patients, reported low adverse event rates of
less than 0.21%.4 It is also postulated that as Avastin is a larger
molecule, it may remain in the eye longer than Lucentis and therefore
allow for less frequent injections. On the other hand. manufacturing
standards do differ: for intra-ocular formulations, particulate matter has
to be very low and Avastin is not manufactured with that in mind.
From a cost point of view, Lucentis could be over 30 times more
expensive than Avastin. One health technology assessment published last
year concluded that due to the price differentials, Avastin would be more
cost effective even if there were differences in effectiveness and side-
effects.(9) This view is supported by cost effectiveness modelling which
showed that Lucentis would need to be 2.5 times more effective than
Avastin in terms of visual acuity.(10) The modelling estimated that the
annual cost to the NHS for treating 25,000 new cases of AMD annually would
be £300 million for Lucentis compared to £8 million for Avastin.
NICE unfortunately is unable to consider Avastin as it can only
assess drugs for their licensed purpose. The question then is why Avastin
has not got a license for intra-ocular use in the UK. Genentech, the
company that manufactures both Avastin and Lucentis has been reluctant to
apply for a license for Avastin for AMD. This is perhaps unsurprising as
it is in a position of imperfect agency and stands to make considerable
financial gains from Lucentis.
Health commissioners face a dilemma between choosing Lucentis, where
there is reasonably good evidence for clinical effectiveness and safety
but with a high cost, versus Avastin which is considerably cheaper and
more affordable but lacking in enough evidence to support its use. The new
NICE position obliges local commissioners to use Lucentis, and will no
doubt be trumpeted by patient groups as a victory for patients. However,
it is a hollow victory as cash-strapped Primary Care Trusts, often
“villainized” by the media for their Scrooge-like tendencies, will now be
under more pressure than before to find resources with which to fund this
costly treatment. The redistribution of resources invariably could imply
other services suffering as a consequence. Where some patients gain,
others will no doubt lose out. The only real winners are the makers of
Lucentis.
References
1. National Institute for Health and Clinical Excellence (2008).
Press release : 2008/052 NICE issues final guidance on the use of
ranibizumab and pegaptanib for the treatment of age-related macular
degeneration (AMD). London: NICE.
2. National Institute for Health and Clinical Excellence (2008).
Macular degeneration (age-related) – pegaptanib and ranibizumab: Appraisal
consultation. London: NICE.
3. Drugs and Therapeutics Bulletin. A view on new drugs for macular
degeneration. Drugs and Therapeutics Bulletin 2007; 45 (7):49-52.
4. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal
Bevacizumab Safety Survey: using the internet to assess drug safety
worldwide. Br J Ophthalmol 2006; 90:1344-1349.
5. International Council of Ophthalmology International Clinical
Guidelines. Age-related Macular Degeneration (Management Recommendations).
April 2007
http://www.icoph.org/guide (Accessed 4/4/08)
6. Spaide RF et al. Intravitreal bevacizumab treatment of choroidal
neovascularization secondary to age-related macular degeneration. Retina.
2006 Apr; 26(4):383-90.
7. Maturi RK et al. Electrophysiologic findings after intravitreal
bevacizumab (Avastin) treatment. Retina. 2006 Mar; 26(3):270-4.
8. Avery RL et.al. Intravitreal bevacizumab (Avastin) for neovascular
age-related macular degeneration. Ophthalmology. 2006 Mar; 113(3):363-372
e5.
9. Wild C, Adlbrecht Ch. Rapid Assessment LBI-HTA 02: Avastin for age
-related macular degeneration. Ludwig Boltzmann Institut fuer Health
Technology Assessment (LBIHTA), 2007. http://eprints.nta.lbg.ac.at/718/
(Accessed 4/4/08)
10. Raftery J, Clegg A, Jones J, et.al. Ranibizumab (lucentis) versus
bevacizumab (avastin): modelling cost effectiveness. Br J Ophthalmol 2007.
Competing interests:
None declared
Competing interests: No competing interests