Clinical trials established in 2005 the efficacy of Ranibizumab (Lucentis, Genentech) for the treatment of neovascular age-related macular degeneration (wetAMD), the leading cause of legal blindness in the United States.This disease is affecting people over the age of 65 with a prevalence of 1.6 million and 200000 new cases per year in the USA .While awaiting approval for ranibizumab from the Food and Drug Administration, ophthalmologists began treating neovascular AMD with off-label use of bevacizumab (Avastin, Genentech), since the drug had a target specificity similar to that of ranibizumab and was available at low cost for about 50$ per monthly injection Vs 1950$ for Lucentis monthly injection. Ranibizumab received the FDA approuval in 2006 to treat specifically the wetAMD,there was a huge debate about the cost effectiveness and the reimbursement of Lucentis in comparaison with Avastin for treating the eye disease. This paper explores the dilemma from different angles.First,it make the emphasize on the need of realizing a head to head comparative study between the two drugs and the means to finance and to launch this study since many roadblocks have been identified. Then, it explores and analyzes the Genentech reaction facing this problem and their strategy to emphasize on the higher risk of death with Avastin, as compared to Lucentis in one hand and in the other hand their strategy to extend the ophthalmologic indications for Lucentis, including diabetic macula edema (DME). Finally it explores what value should be put on safety in health technology assessments HTAs by developing that we can’t just consider the dollar value of medicine alone but we need to consider the cost of adverse events caused by the treatment and the cost of living with these adverse events

1. Chair of Therapeutic Innovation
Genentech’s Dilemma :Avastin VS. Lucentis
Jemaa Nejmeddine
30/01/13

2. Table des matières
Executive Summary 3
Introduction: 4
Establishing a comparative-effectiveness Research : 5
Genentech and Novartis Reaction: 6
What value should be put on safety? 7
Conclusion 8

3. Executive Summary
Clinical trials established in 2005 the efficacy of Ranibizumab (Lucentis, Genentech) for the
treatment of neovascular age-related macular degeneration (wetAMD), the leading cause of
legal blindness in the United States.This disease is affecting people over the age of 65 with a
prevalence of 1.6 million and 200000 new cases per year in the USA .While awaiting
approval for ranibizumab from the Food and Drug Administration, ophthalmologists began
treating neovascular AMD with off-label use of bevacizumab (Avastin, Genentech), since the
drug had a target specificity similar to that of ranibizumab and was available at low cost for
about 50$ per monthly injection Vs 1950$ for Lucentis monthly injection.
Ranibizumab received the FDA approuval in 2006 to treat specifically the wetAMD,there was
a huge debate about the cost effectiveness and the reimbursement of Lucentis in comparaison
with Avastin for treating the eye disease.
This paper explores the dilemma from different angles.First,it make the emphasize on the
need of realizing a head to head comparative study between the two drugs and the means to
finance and to launch this study since many roadblocks have been identified.
Then, it explores and analyzes the Genentech reaction facing this problem and their strategy
to emphasize on the higher risk of death with Avastin, as compared to Lucentis in one hand
and in the other hand their strategy to extend the ophthalmologic indications for Lucentis,
including diabetic macula edema (DME).
Finally it explores what value should be put on safety in health technology assessments HTAs
by developing that we can’t just consider the dollar value of medicine alone but we need to
consider the cost of adverse events caused by the treatment and the cost of living with these
adverse events

4. Introduction:
Age-related macular degeneration (AMD) is a condition affecting older people (over the age
of 65), and involves the loss of the person's central field of vision. It occurs when the macular
retina develops degenerative lesions. It is thought that circulatory insufficiency, with
reduction in the blood flow to the macular area, also plays a part. The AMD is the third
leading cause of blindness after cataract and glaucoma. In the US, more than 1.6 million
people are affected with AMD and there are approximately 200,000 new cases diagnosed
each year.
In 2005, clinical trials established the efficacy of Ranibizumab (Lucentis®,Roche/Genentech)
for the treatment of neovascular age-related macular degeneration (AMD) also called
wetAMD which is a several form of AMD . While awaiting approval for Ranibizumab from
the Food and Drug Administration, ophthalmologists began treating neovascular AMD with
off-label use of Bevacizumab (Avastin®, Genentech), since the drug had a target specificity
similar to that of Ranibizumab and was available at low cost about 50$ per monthly injection .
Intraocular administration of bevacizumab is entirely off-label because the drug is formulated
for intravenous infusion and had received a label in 2004 for treating metastaic colo rectal
cancer. Nonetheless, and though data from controlled trials are lacking, bevacizumab appears
to be safe and effective in the short term, and ophthalmologists frequently use medications
off-label
In July 2006 On June 30, 2006, the Food and Drug Administration (FDA) approuved Lucentis
for the treatment of wAMD. Ranibizumab is a fragment of a recombinant monoclonal
antibody that binds to and inhibits all the biologically active forms of vascular endothelial
growth factor A. Administered by injection into the vitreous cavity, Ranibizumab prevents
vision loss in 95% improves visual acuity and bring back vision 1 in 3 of the cases, with few
serious adverse effects (results published in The New England Journal of Medicine) ; it thus
represents a substantial advance against a leading cause of blindness.
Ranibizumab was developed by both Genentech and Novartis and as a result, Genentech
commercialized the drug in North America for 1950$ per month and Novartis commercialized
it in the rest of the world and especially Europe for 1200€.
In mid 2007 Genentech declared that Avastin would be no longer be sold to compounding
pharmacies, that is ,the intermediate that split the product (100 mg single use vial) into
multiple dose for off-label use.
Facing this dilemma many questions were posed: the need of conducting a head to head
comparative trial between the two treatments isn’t important to resolve the situation? And
who will pay for these trials?
What is the position of Genentech and Novartis about this trials and how they will react?
How this debate will impact on Health Policy System in the different countries concerned?
Will this revive the debate about The value of Safety in health policy?

5. Establishing a comparative-effectiveness Research :
Patient-advocacy and health policy groups have hailed comparative-effectiveness research
(CER) as a means of reducing health care costs without compromising the quality of care. The
federal commitment of $1.1 billion under the American Recovery and Reinvestment Act
(ARRA) ensures that the scientific community will undertake considerable amounts of such
studies. Researchers have conducted comparative efficacy studies of drugs or medical devices
and such interventions are intended to reduce healthcare costs and reward “true” innovation.
In the reality an efficient major federal policy change and innovative measures were required
before one CER study, Comparison of AMD Treatments Trials (CATT) could even be
launched. With no pharmaceutical company sponsoring the study the road to achieve this
study was complicated.
In the beginning as the US National eye institute grant covered the $1 million cost for the
purchase, repackaging, and distribution of Bevacizumab, but the problem reside in financing
the 25 million needed for purchasing Ranibuzumab which has received FDA approval and so
a revising of Medicare Clinical Trial Policy of July 2007 had explicitly extended coverage to
drugs under investigation if they were normally covered outside of the trial.
Then there were other roadblocks to be overcome,the estimated 15% of Medicare
beneficiaries who do not have supplemental insurance are responsible for a 20% copayment
for drugs and if drugs being compared in a trial cost different amounts, copayments will also
differ. Such increased costs may lead patients to refuse treatment as their bills accumulate or
to switch to the less expensive drug, thereby which compromise the integrity of the study.
Fortunately, the NIH Grants Policy Statement does outline exceptional circumstances and
guiding principles for cases in which special reimbursement procedures can be adopted to
meet a unique need. This flexibility allowed the NEI to allocate grant funds to cover the
residual copayments for the study drug after the supplemental insurance companies had been
billed.
Finally CATT enrollment began in February 2008, and the enrollment goal of 1200 patients
was achieved in December 2009. The roadblocks delayed study initiation by more than a year,
while another 200,000 patients and their doctors had to make decisions without important
information about relative efficacy and safety.
Discussion:
Despite the efforts, there is still insufficient infrastructure for the implementation of federally
sponsored CER trials. I believe that the Federal Coordinating Council for Comparative
Effectiveness Research must regard these issues, and the insurance industry should be called
on to facilitate CER trials. A comprehensive federal policy that would cover all drug-related
costs and evade the need to rely on current billing and payment mechanisms would greatly
simplify the planning and execution of CER trials. Without such a policy, it is difficult to
imagine that the $1.1 billion of ARRA funding for CER will be used effectively.

6. In France, a new committee has been launched in July 2008 called “Comission évaluation
économique et de Santé Publique (CEESP)” with aim to realize medico-economic and
comparative drug studies with the existing molecules which permit an efficiency assessment.
Genentech and Novartis Reaction:
The one-year follow-up results of the CATT study were released in 2011. The primary
outcome was the mean change in visual acuity at one year. Avastin was equivalent to Lucentis
for vision acuity. Rates of death, myocardial infarction, and stroke were similar for patients
randomized to either Avastin or Lucentis.
Although Genentech respectfully declined to contribute to the funding or logistics of the
CATT study, they were interested in the results and shaping the subsequent debate. The New
York Times (10/03/10) has reported that Roche/Genentech has responded to the publicity of
the trial by offering rebates on Lucentis, based on volume. For example, rebates range from
0.25% to 1.5% of wholesale cost: using 600 vials yields a rebate of $8,775.
Roche pointed up correctly that while the CATT study was powered statistically to test the
two biologic agents in terms of efficacy, the study was not powered to test for potential
differences in safety, which would likely required thousands of AMD patients.
Indeed, Roche commissioned its own study of 78,000 Medicare recipients with AMD, treated
with Avastin or Lucentis, and observed an 11% increased mortality among users assigned to
Avastin compared to Lucentis users.
Discussion:
It is obvious that Roche would be willing to play-up the safety angle of Lucentis versus
Avastin, in the endevaor to defend the equivalent of $1.52 billion US that Lucentis generated
in 2010 to treat AMD for Roche in the US (roche.com, 1/27/11). Although Lucentis
generated an additional $1.54 billion US in 2010 registered by Novartis
(bernstein.com/Anderson, 1/31/11), based on international sales of Lucentis.
In contrast, Avastin generated the equivalent of $6.72 billion US in 2010, and is already at the
center of a firestorm based on the inability to deliver a survival advantage in advanced breast
cancer. Hence, the US regulators threat to remove Avastin’s labeling to treat advanced breast
cancer.
In this context then, it is a dangerous strategy that Roche is adopting, emphasizing on the
higher risk of death with Avastin, as compared to Lucentis, in the epidemiologic study of
Medicare patients diagnosed with AMD. This strategy can backfire, making safety concerns
with Avastin more salient.

7. By the same time Roche and Novartis have focused on expanding the ophthalmologic
indications for Lucentis, including diabetic macula edema (DME) which is the most common
cause of vision loss in working-age Americans. Lucentis was approved in 2011 for treatment
of visual impairment due to DME in Europe, where it is marketed by Novartis and Roche is
waiting for US approval for this supplemental indication. I think that this extension of
indication will reinforce the efficiency and reliability of Ranibizumab for macular disease as
the drug was conceived in that aim unlike Avastin which was conceived to treat solid cancer.
What value should be put on safety?
For most countries there is a growing awareness that drug costs are spiraling out of control.
Health Technology assessments (HTAs) evaluate cost effectiveness internationally.
Arguably, the most influential is the National Institute for Health and Clinical Excellence
(NICE) in the UK.
Prior to the release of the CATT study results, a model was constructed comparing the cost
effectiveness of Avastin versus Lucentis to achieve a £30k per Quality Adjustment Life Years
QALY, a NICE threshold equivalent to about $50,000 US per QALY. The NICE has
accepted Lucentis as cost effective in the treatment of AMD, based on a risk-sharing deal with
Novartis. The deal negotiated entails the National Health Service (NHS) paying for a
maximum of 14 injections, per eye, for patients with wet AMD Addi-tional treatments, if
necessary, will be paid by Novartis.
Taking the US for example a study has recently within Medicare, established off-label use of
Avastin count for nearly 60% of their AMD injections, as compared with about 40% for
Lucentis (online.wsj.com). In terms of revenue, in contrast, Medicare paid $537 million for
Lucentis in 2008 versus only $20 million for Avastin. This is due to the differential pricing,
Medicare paid on average $50 a dose for Avastin in the eye, as compared with $1,950 a dose
for Lucentis.
As a consequent a single dose of Ranibizumab costs 40 times as much as a single dose of
Bevacizumab. This cost differential has important economic implications when extrapolated
to the more than 250,000 patients who are treated for wetAMD annually in the United States.
Many other countries adopted the same strategy but I don’t think that we can just consider the
dollar value of medicine alone. In fact, we need to consider the cost of adverse events like
severe eye inflammation or stroke which are responsible for hospitalization, we need also to
consider the human cost of living with this adverse events. Since we know that these adverse
events has 12 more times chance to appear (according to Canadian journal of ophthalmology)
with Avastin comparing to Lucentis which is a huge rate, it is obvious that safety issue need
to be part of health policy debate.

8. One example of the reality today is the scandal off-label use of contraceptive pill of 3rd
generation Diane 35 for treating acne which provokes many adverse events and the death of 5
persons in France. This is emphasizing the importance of the value of safety nowadays in offlabel drug because patient association are willing to sue responsible for this type of scandal
and the health authorities are reacting too late facing this kind of problem. Besides such kind
of dilemma lead us to the fundamental oath of Hippocrate in medicine “Primum non nocere
deinde curare”
Conclusion
Combining revenue from the two biologic agents, Avastin and Lucentis, the result is
approximately $9.7 billion in global sales in 2010, and arguably the second leading drug in
sales behind Pfizer’s Lipitor.
The successful CATT study of Avastin versus Lucentis in AMD, demonstrating no clinical
differences between treatment arms in efficacy may be to launch a more active role by
governments in the US and internationally to design clinical trials aimed at evaluating
initiating the empirical evidence for reducing pharmaceutical budgets. This version of
comparative effectiveness research may ultimately be the larger threat to the pharmaceutical
industry.
As with global fight against AIDS the goal is to make affordable drugs available to most
people affected with the disease but the problem is that we want to go so fast that we forget
about an important factor which is the Safety. We should keep in mind that full knowledge is
rarely available before a decision but the best available knowledge need to be known.