BMJ 2012;344:e2941 doi: 10.1136/bmj.e2941 (Published 1 May 2012) Page 1 of 3
Analysis
ANALYSIS
Implications of “not me” drugs for health systems:
lessons from age related macular degeneration
The debate surrounding the use of new drugs for age related macular degeneration has sparked
worldwide controversy. Robert Campbell and colleagues highlight how differing funding systems
have affected use of these drugs in different countries and suggest how to deal with similar challenges
in future
1 2
Robert J Campbell assistant professor , Irfan A Dhalla assistant professor , Sudeep S Gill associate
3 2
professor , Chaim M Bell associate professor
1
Department of Ophthalmology, Hotel Dieu Hospital and Queen’s University, 166 Brock Street, Kingston, Ontario, Canada K7L 5G2; 2Department
of Medicine, St Michael’s Hospital and the University of Toronto, Toronto, Ontario, Canada; 3Division of Geriatric Medicine, St Mary’s of the Lake
Hospital and Queen’s University, Kingston
The journey of a new drug from laboratory to market is long which has a key role in the growth of these pathological vessels.3
and expensive, and particularly treacherous for a drug with a w7-w10
They are the first treatments to consistently and
novel mechanism of action. Only a small proportion of truly substantially improve vision in patients with AMD.4-7
innovative new drugs find their way into our therapeutic While ranibizumab was developed and approved for intravitreal
armamentarium, and the success of these innovative drugs often injection to treat AMD,w7 w9 bevacizumab has been approved
inspires the proliferation of “me-too” drugs—products developed only for intravenous use as a cancer therapy.w11 Ranibizumab
to target a pathway of known viability.1 w1 is a smaller molecule than bevacizumab and consists of only
Recently, however, two drugs sharing a novel mechanism, the antigen binding fragment of the parent antibody. It was
ranibizumab (Lucentis) and bevacizumab (Avastin), have been hypothesised that ranibizumab would penetrate the retina better
licensed for different indications, and the manufacturer is trying and cause less inflammation than bevacizumab.w7-w9 However,
to keep their uses distinct. Although both drugs have been shown before phase III trials of ranibizumab were completed,
to be effective for the treatment of age related macular physicians began using bevacizumab off-label for AMD,
degeneration (AMD), a leading cause of blindness in high reasoning that the molecular target was the same for both
income countries, only ranibizumab has been approved by the drugs.w12 Subsequently, the obvious efficacy of bevacizumab
US Food and Drug Administration for this indication.2 Both resulted in its rapid adoption in many countries.8 9
drugs were developed by Genentech, which was acquired by
Roche in 2009, with Novartis holding the licence to sell Comparative efficacy and safety
ranibizumab outside of the US. However, ranibizumab is much
more expensive than bevacizumab when used to treat AMD. Until recently, high quality data showing that bevacizumab is
The companies’ active discouragement of the use of effective in AMD were lacking, and this information gap heavily
bevacizumab for macular degeneration—creating a “not me” influenced treatment decisions made by patients, clinicians, and
drug—has focused attention on important aspects of drug policy. policy makers. However, in 2011 a National Institutes of Health
In particular, how differing health financing systems have sponsored trial comparing the two drugs for AMD (the
contributed to the wide variation in uptake of ranibizumab and Comparison of Age-Related Macular Degeneration Treatment
bevacizumab for AMD among high income countries. Trials (CATT)) reported that bevacizumab and ranibizumab
provide similar safety and efficacy.7 Additional studies will
Pharmacology of new drugs report in the near future, including the IVAN (alternative
Most cases of severe vision loss in AMD are caused by the treatments to Inhibit VEGF in Age related choroidal
proliferation of abnormal blood vessels beneath and within the Neovascularisation) trial in the UK. However, these trials were
retina.2 w2 Both ranibizumab and bevacizumab are monoclonal not powered to detect small but clinically relevant differences
antibodies directed against vascular endothelial growth factor, in adverse outcomes such as stroke, which could result from
Correspondence to: R J Campbell rob.campbell@queensu.ca
Extra references w1-w35 supplied by the author (see http://www.bmj.com/content/344/bmj.e2941?tab=related#webextra)
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BMJ 2012;344:e2941 doi: 10.1136/bmj.e2941 (Published 1 May 2012) Page 2 of 3
ANALYSIS
the differing systemic absorption and half lives of the two is 65 years of age and older, fund ranibizumab but not
drugs.w10 w13 Ongoing post-marketing observational studies will bevacizumab. As a result, use of ranibizumab in Ontario is four
need to examine these safety concerns. times the rate seen in the US Medicare population.8 9
Other jurisdictions with structured third party payer drug
Comparative cost evaluation processes have taken an alternative approach, and
have bypassed these processes altogether. For instance, the
The quantity of bevacizumab administered by intravitreal
Canadian province of British Columbia covers intravitreal
injection in AMD is much less than that used intravenously in
injections of bevacizumab through the publicly funded
cancer treatment. As a result, the current price for bevacizumab
Provincial Health Services Authority, which is not strictly
is £30-£50 (€37-€62; $50-$80) per injection.7 w2 In contrast, the
subject to the usual evaluation processes for listing a drug on
current price of ranibizumab is about £1250 per injection.7 Since
the formulary of medications that the province covers.w26 While
most patients require monthly injections for extended periods,
pragmatic, this approach may be difficult to replicate in other
the absolute difference in total expenditures is usually thousands
jurisdictions and may not provide for consistent and transparent
of pounds per patient.8 10
decision making.
In the UK, as in the US and Canada, coverage and use of
Regulatory approval, third party payers, bevacizumab varies by jurisdiction, with primary care trusts
and treatment choice formulating their own policies.w27 w28 Hence, the UK Department
of Health, through the National Institute for Health and Clinical
Typically, manufacturers design, conduct, and pay for clinical
Excellence (NICE), has begun working towards formally
trials that provide data used by regulatory agencies when
evaluating bevacizumab for AMD.19 w29 This has required
assessing a drug’s efficacy, safety, and quality. If a manufacturer
substantial new collaborative efforts and the development of
does not want a drug to be used for a different indication from
new processes. In particular, NICE has led consultations to
which it was licensed for, it can discourage use by not applying
evaluate the feasibility of formally appraising bevacizumab for
for regulatory approval for that indication, limiting supply, and
AMD. This consultation was carried out at the request of the
questioning the drug’s safety and efficacy.1 11 12 w1 w17 w18 Although
UK Department of Health and involved representation from
bevacizumab for AMD is probably the first example of a “not
government, primary care trust administration, industry, doctors,
me” drug, the proliferation of expensive biological drugs and
and patients. The Department of Health is expected to ask NICE
industry takeovers of competitors have the potential to create
to proceed with a formal assessment after the results of the
similar situations in which a company is motivated to discourage
IVAN trial are published. The outcomes of these novel policy
the use of one of its own drugs to increase sales of another.
directions should serve as an important learning opportunity for
Most patients with AMD who have to pay their own prescription jurisdictions with centralised formularies and may help guide
costs choose bevacizumab over ranibizumab, even though it US Medicare national coverage determination processes as well.
does not have regulatory approval.8 With the potential to save
billions of dollars, many third party payers, both public and
private, are also keen to use the cheaper drug. For example, US
Rational drug choices
Medicare covers both bevacizumab and ranibizumab for AMD. While economic evaluations have supported the adoption of
Additionally, Medicare contractors and the Centers for Medicare bevacizumab for AMD,w30 regulators have been challenged by
and Medicaid Services (CMS) have recognised the costs the unprecedented unwillingness of the drug’s manufacturer to
associated with dividing bevacizumab into small quantities for submit an application for its use in AMD. However, third party
intraocular injection in the fees they pay to physicians.13 14 w19 payer coverage of bevacizumab, not regulatory approval, will
Most coverage decisions for Medicare are made by regional be the primary factor determining treatment, as shown by its
for-profit carriers, w20 and this seems to have provided the widespread use in some jurisdictions. Further, major moves to
latitude and motivation to cover off-label bevacizumab.15 With facilitate access to bevacizumab are taking place among payers
both drugs covered by Medicare, drug copayments make and cost effectiveness evaluators including the CMS, NICE,
ranibizumab much more expensive for Medicare patients. and Canadian provincial drug programmes. In response, Novartis
Consequently, bevacizumab is used in about 60% of injections launched legal action this month in the UK aimed at forcing
for AMD in this population.9 hospitals to use ranibizumab.20
Despite considerable use of bevacizumab, ranibizumab sales in Several other factors may also influence the decision to choose
the US still surpassed $1.8bn in 2010, which will propel bevacizumab or ranibizumab. Although CATT has shown
ranibizumab into the single greatest drug expenditure under bevacizumab and ranibizumab to be of similar efficacy and
Medicare Part B.16 w21 This suggests that many US patients are safety in a trial setting, numerous instances of infection have
either insensitive to the price of ranibizumab because Medicare been reported in general use, probably because of suboptimal
covers the majority of the cost (with private insurance potentially infection control practices during the repackaging of
covering copayments) or that US patients face barriers to bevacizumab for intravitreal injection.21 This recently prompted
accessing bevacizumab for AMD. In response, public leaders the US Veterans Administration healthcare system to suspend
have recently requested a national coverage determination coverage of bevacizumab for AMD.w31
supporting the use of bevacizumab for AMD in order to improve Fear of litigation from patients with rare but serious adverse
access to care.w22 events,w32 w33 and fear of legal action by industry, as has occurred
In contrast to the US Medicare system, many public formularies in Germany,w17 may also provide disincentives to the use of
in countries with centralised, structured drug review processes bevacizumab. These fears are especially influential in systems
such as the UK, Canada, and Australia have been constrained with third party payers, where neither the patient nor the doctor
by the fact that they generally only pay for drugs that have been is responsible for costs but they both bear the risks of adverse
granted regulatory approval for the covered indication.17 18 w23 outcomes and litigation.
w24
For example, the Ontario Public Drug Programs, which pay Financial considerations may also influence doctors’ choices.
for prescription medications for everyone in the province who Genentech has paid US doctors who give large numbers of
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BMJ 2012;344:e2941 doi: 10.1136/bmj.e2941 (Published 1 May 2012) Page 3 of 3
ANALYSIS
ranibizumab injections.22 Furthermore, Medicare part B wrote the first draft of the manuscript. IAD, SSG, and CMB revised the
reimbursement to physicians for drugs is directly proportional draft. All authors approved the submitted version. RJC is the guarantor.
to the price of the drug used, and physicians are able to retain Competing interests: All authors have completed the ICMJE competing
a portion of this reimbursement as income.10 w34 Without this interests form at www.icmje.org/coi_disclosure.pdf (available on request
unintended incentive to use ranibizumab, US Medicare policy from the corresponding author) and declare: RJC is supported by a
would likely be even more effective in promoting the use of clinician scientist award from the Southeastern Ontario Academic
bevacizumab. Medical Organization which receives funding from the Ontario Ministry
of Health and Long-Term Care (MOHLTC) and holds research grants
Lessons and future directions from the Canadian Institutes of Health Research (CIHR) and the
MOHLTC for related work; SSG is supported by a CIHR new investigator
The use of public funds to support comparative trials of award from the Institute of Aging; CMB is supported by a CIHR and
bevacizumab and ranibizumab, such as the CATT and IVAN Canadian Patient Safety Institute chair in patient safety and continuity
trials, was predicated on the notion that the less expensive option of care. The authors have no financial relationships with any
would be preferred if the drugs were of equivalent efficacy. organisations that might have an interest in the submitted work in the
Despite the results of the CATT study, ranibizumab remains previous three years; all authors are present or past board members or
the dominant therapy in jurisdictions such as Ontario, where it expert advisers to the MOHLTC Committee to Evaluate Drugs.
is fully reimbursed by public drug programmes, and maintains
Provenance and peer review: Not commissioned; externally peer
a surprisingly large market share in others, such as the US
reviewed.
Medicare population, even though patients are at least partially
exposed to price. Clearly, appropriate authorities, policies, and 1 Lee T. “Me-Too” products: friend or foe? N Engl J Med 2004;350:211-2.
processes are needed to ensure that bevacizumab is available, 2 Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med
that there is a structure in place that ensures accountability for 2008;358:2606-17.
3 Ip MS, Scott IU, Brown GC, Brown MM, Ho AC, Huang SS, et al. Anti-vascular endothelial
drug safety and quality, and that patients are making fully growth factor pharmacotherapy for age-related macular degeneration—a report by the
informed choices. American Academy of Ophthalmology. Ophthalmology 2008;115:1837-46.
4 Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab
Support for the use of bevacizumab from professional versus verteporfin for neovascular age-related macular degeneration. N Engl J Med
organisations such as the American Academy of Ophthalmology, 5
2006;355:1432-44.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab
the Royal College of Ophthalmologists, and the Canadian for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31.
Ophthalmological Society would provide doctors with a clear 6 Tufail A, Patel PJ, Egan C, Hykin P, da Cruz L, Gregor Z, et al. Bevacizumab for
neovascular age related macular degeneration (ABC trial): multicentre randomised double
definition of the standard of care, and might help to allay fears masked study. BMJ 2010;340:c2459.
of legal liability arising from off label use of bevacizumab.w35 7 CATT Research Group, Martin DF, Maguire MG, Ying G, Grunwald JE, Fine SL, et al.
Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N
In many instances, uptake of bevacizumab for AMD will also Engl J Med 2011;364:1897-908.
require health technology assessors such as NICE and the CMS 8 Campbell RJ, Bronskill SE, Bell CM, Paterson JM, Whitehead M, Gill SS. Rapid expansion
to validate its use. of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis. Arch
Ophthalmol 2010;128:359-62.
Another barrier to use in North America and the UK, is that 9 Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular
age-related macular degeneration: an analysis of the 100% 2008 Medicare fee-for-service
both drug and physician regulatory bodies have policies that Part B claims file. Am J Ophthalmol 2011;151:887-95.
discourage the use of off-label and off-licence therapies. These 10 Levinson DR. Review of Medicare Part B Avastin and Lucentis treatments for age-related
macular degeneration (A-01-10-00514) [internet]. 2011 http://oig.hhs.gov/oas/reports/
well intentioned policies were created because evidence region10/11000514.pdf.
supporting most off-label drug uses is lacking. By contrast, the 11 Pollack A. Maker seeks to restrict cancer drug use on eye New York Times 2007 Oct 12.
www.nytimes.com/2007/10/12/business/12eye.html?ref=avastindrug.
level of evidence supporting the use of bevacizumab in AMD 12 Novartis. New analysis representing largest available dataset highlights relative safety of
is of the highest quality.6 7 Hence, such policies should be refined Lucentis (ranibizumab) compared to unlicensed intravitreal Avastin (bevacizumab). Press
to allow for a case by case evaluation of evidence. release, 4 May 2011. www.novartis.com/newsroom/media-releases/en/2011/1512519.
shtml.
The process of designing appropriate, precedent setting 13 Pollack A. A rule on eye treatment is likely to cost millions. New York Times 2009 Oct 1
www.nytimes.com/2009/10/02/business/02avastin.html.
responses to the bevacizumab-ranibizumab conundrum could 14 Aron I. Avastin/Lucentis Update 33: the wording of the CMS order for repricing of Avastin.
be made more comprehensive and efficient through international 2009. http://irvaronsjournal.blogspot.com/2009/11/avastinlucentis-update-33-wording-of.
html.
communication among health technology assessors, as well as 15 Foote SB, Wholey D, Rockwood T, Halpern R. Resolving the tug-of-war between
among drug and physician regulatory bodies. With enhanced Medicare’s national and local coverage. Health Aff 2004;23:108-23.
recognition that drug policies have influenced the uptake and 16
17
Roche. Finance report 2010. www.roche.com/investors/annual_reports.htm.
Clement FM, Harris A, Li JJ, Yong K, Lee KM, Manns BJ. Using effectiveness and
costs of bevacizumab and ranibizumab in countries such as the cost-effectiveness to make drug coverage decisions. JAMA 2009;302:1437-43.
UK, the US, and Canada, improved sharing and dissemination 18 Levy AR, Mitton C, Johnston KM, Harrigan B, Briggs AH. International comparison of
comparative effectiveness research in five jurisdictions: insights for the US.
of detailed information on new policies and their effects could Pharmacoeconomics 2010;28:813-30.
guide evidence informed healthcare internationally. 19 National Institute for Health and Clinical Excellence. Exploratory work of bevacizumab in
eye conditions. 2010. www.nice.org.uk/ourguidance/niceguidancebytype/
technologyappraisals/proposedappraisals/bevacizumabineyeconditions.jsp.
We thank Erica Campbell MD, MHA for help with preparing the 20 Novartis takes legal action over trusts’ advice to use bevacizumab for wet AMD. BMJ
2012;344:e2959
manuscript. 21 Pollack A. Doctors grow wary of Avastin for eye treatment. New York Times 2011 Oct 4.
Contributors and sources: All authors are practising physicians and are http://prescriptions.blogs.nytimes.com/2011/10/04/doctors-grow-wary-of-avastin-for-eye-
treatment/.
past or present members of, or advisers to the Ontario Committee to 22 Pollack A. Genentech offers secret rebates for eye drug New York Times 2010 Nov 3.
Evaluate Drugs, which makes recommendations to the Ministry of Health www.nytimes.com/2010/11/04/business/04eye.html?pagewanted=all.
and Long-Term Care (MOHLTC) in Ontario regarding which drugs Accepted: 16 February 2012
should be paid for publicly. The opinions expressed here are those of
the authors. RJC, CMB, and SSG have published on the use of VEGF Cite this as: BMJ 2012;344:e2941
inhibitors for AMD. RJC is director of ophthalmology postgraduate © BMJ Publishing Group Ltd 2012
residency education at Queen’s University, Kingston, Ontario. RJC
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