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THERAPEUTIC REVIEWS JOEL S. MINDEL, EDITOR Position Paper: The Need for Head-to-Head Studies Comparing Avastin versus Lucentis Christine Schmucker, PhD, 1 Gerd Antes, PhD, 1 and Monika Lelgemann, MD, MSc 2 1 German Cochrane Center, University Medical Center Freiburg, Germany; and 2 Health Technology Assessment Center, University Bremen, Germany The ophthalmological world is on edge as the title holder for the treatment of exudative age-related macular degeneration (AMD) is under threat from an apparent amateur. These two challengers have yet to compete head-to-head under the same (study) conditions. Both competitors, ranibizumab (trade name Lucentis) and bevacizumab (trade name Avastin) are vascular endothelial growth factors (VEGF) inhibitors and both are derived from the same monoclonal antibody. However, ranibizumab, which is an antibody fragment from the bevacizumab molecule with an increased binding affinity for all forms of VEGF, has been approved for the treatment of all angiographic subtypes of subfoveal neovascular AMD by the U.S. Food and Drug Administration and by the Euro- pean Medicines Agency since 2006 and 2007, respectively. The approval was based on two ran- domized controlled trials which showed that ap- proximately 95% of the patients treated with monthly ranibizumab injections lost fewer than 15 letters in 12 months, compared to 64% of patients receiving photodynamic therapy (PDT) and 62% receiving sham treatment. 3,12 In addition, approxi- mately every third patient showed improvements in visual acuity. Serious ocular adverse effects under monthly ranibizumab injections were in the order of 1--2% over a 2-year treatment period. 12 In sharp contrast to ranibizumab, bevacizumab was not developed for the treatment of AMD and consequently has no approval for this use. Bevaci- zumab is approved for the treatment of specific cancers—for example, metastatic colon and rectum cancer. Even before ranibizumab was licensed, bevacizumab had been used as an off-label treat- ment for AMD; however, the efficacy and safety of intravitreal bevacizumab have not yet been suffi- ciently evaluated. The existing randomized stud- ies 2,8,11,13,15 do not meet the quality requirements of phase III trials. Validity is limited by small sample sizes (between 28 and 165 patients per study), short follow-up times, inadequate masking, lack of stan- dardized vision measurements, and missing inten- tion-to-treat analyses. Compared with PDT, bevacizumab shows a relative improvement in visual acuity that is of similar size as the comparison of ranibizumab with PDT (relative improvement 30% to 35%), 2 but this is based on less than 50 patients. Therefore, any conclusion regarding efficacy is of limited validity, and no conclusions can be drawn about safety aspects. Also, nothing is known about long-term (O12 months) improvements in visual acuity and optimal treatment intervals for bevacizumab. The apparent advantages of ranibizumab in comparison to bevacizumab are not so attractive if costs are considered. Monthly injections of 0.5 mg ranibizumab cost more than US$ 23,000 per patient annually. 14 Depending on the number of patients who would require ranibizumab, the immense costs 705 Ó 2009 by Elsevier Inc. All rights reserved. 0039-6257/09/$--see front matter doi:10.1016/j.survophthal.2009.08.002 SURVEY OF OPHTHALMOLOGY VOLUME 54 NUMBER 6 NOVEMBER–DECEMBER 2009

Position Paper: The Need for Head-to-Head Studies Comparing Avastin versus Lucentis

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SURVEY OF OPHTHALMOLOGY VOLUME 54 � NUMBER 6 � NOVEMBER–DECEMBER 2009

THERAPEUTIC REVIEWSJOEL S. MINDEL, EDITOR

Position Paper: The Need for Head-to-Head StudiesComparing Avastin versus LucentisChristine Schmucker, PhD,1 Gerd Antes, PhD,1 and Monika Lelgemann, MD, MSc2

1German Cochrane Center, University Medical Center Freiburg, Germany; and 2Health Technology Assessment Center,University Bremen, Germany

The ophthalmological world is on edge as the titleholder for the treatment of exudative age-relatedmacular degeneration (AMD) is under threat froman apparent amateur. These two challengers haveyet to compete head-to-head under the same (study)conditions. Both competitors, ranibizumab (tradename Lucentis) and bevacizumab (trade nameAvastin) are vascular endothelial growth factors(VEGF) inhibitors and both are derived from thesame monoclonal antibody.

However, ranibizumab, which is an antibodyfragment from the bevacizumab molecule with anincreased binding affinity for all forms of VEGF, hasbeen approved for the treatment of all angiographicsubtypes of subfoveal neovascular AMD by the U.S.Food and Drug Administration and by the Euro-pean Medicines Agency since 2006 and 2007,respectively. The approval was based on two ran-domized controlled trials which showed that ap-proximately 95% of the patients treated withmonthly ranibizumab injections lost fewer than 15letters in 12 months, compared to 64% of patientsreceiving photodynamic therapy (PDT) and 62%receiving sham treatment.3,12 In addition, approxi-mately every third patient showed improvements invisual acuity. Serious ocular adverse effects undermonthly ranibizumab injections were in the order of1--2% over a 2-year treatment period.12

In sharp contrast to ranibizumab, bevacizumabwas not developed for the treatment of AMD and

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� 2009 by Elsevier Inc.All rights reserved.

consequently has no approval for this use. Bevaci-zumab is approved for the treatment of specificcancers—for example, metastatic colon and rectumcancer. Even before ranibizumab was licensed,bevacizumab had been used as an off-label treat-ment for AMD; however, the efficacy and safety ofintravitreal bevacizumab have not yet been suffi-ciently evaluated. The existing randomized stud-ies2,8,11,13,15 do not meet the quality requirements ofphase III trials. Validity is limited by small samplesizes (between 28 and 165 patients per study), shortfollow-up times, inadequate masking, lack of stan-dardized vision measurements, and missing inten-tion-to-treat analyses. Compared with PDT,bevacizumab shows a relative improvement in visualacuity that is of similar size as the comparison ofranibizumab with PDT (relative improvement 30%to 35%),2 but this is based on less than 50 patients.Therefore, any conclusion regarding efficacy is oflimited validity, and no conclusions can be drawnabout safety aspects. Also, nothing is known aboutlong-term (O12 months) improvements in visualacuity and optimal treatment intervals forbevacizumab.

The apparent advantages of ranibizumab incomparison to bevacizumab are not so attractive ifcosts are considered. Monthly injections of 0.5 mgranibizumab cost more than US$ 23,000 per patientannually.14 Depending on the number of patientswho would require ranibizumab, the immense costs

0039-6257/09/$--see front matterdoi:10.1016/j.survophthal.2009.08.002

706 Surv Ophthalmol 54 (6) November--December 2009 SCHMUCKER ET AL

would have a significant effect on national healthbudgets. In contrast, the costs for bevacizumab areconsiderably lower. Small aliquots in syringes forintraocular injections can be administered for aboutUS$ 17--50 a month (# US$ 600 annually).14

The cost difference is so striking that the almosttotal lack of sound evidence from rigorouslycontrolled clinical trials is simply ignored. Instead,numerous case series evaluating bevacizumab havebeen published over the last years. Not surprisingly,they show common methodological weaknesses andare of limited validity. For example, out of fiveprospective case series including 241 patients withuntreated AMD,1,5,7,9,10 only one evaluated morethan 100 patients.9 As there is no control group, noreliable conclusions on efficacy can be drawn fromthis study design. Regarding safety, the results of thepublished case series are also of limited valuebecause of inadequate reporting, an unsystematicevaluation of adverse effects, and short follow-uptimes. Data resulting from retrospective case series,for example, the often cited multicenter Pan-American Collaborative Retina Study Grouppublication16 or the international intravitreal bev-acizumab safety survey,6 are of even more limitedvalue mainly because of incomplete6 or short (3.5months) follow-ups6 and self-reported adverse ef-fects.6,16 Thus, the reported low rates of adverseeffects for bevacizumab are not supported byreliable data. It is disappointing that no case serieshave been conducted on a quality level that wouldhave allowed at least a crude estimation of adverseevents under intravitreal bevacizumab.

The choice between a licensed drug that has beenevaluated in rigorously controlled trials and a muchcheaper alternative has led to a practical and ethicaldilemma, as even groups who strongly believe ina regulated drug development process tolerate off-label use. This could also be explained on ethicalgrounds that wasting money in health care isunethical. Nevertheless, it must not be forgottenthat the intravitreal use of bevacizumab is not basedon reliable evidence.

Currently, there are no results of randomized,controlled trials directly comparing the two VEGFinhibitors. As a result of large differences in thestudy quality, a reliable indirect comparison betweenbevacizumab and ranibizumab can also not beperformed.

Differences between ranibizumab and bevacizu-mab are likely. For example, the bevacizumabmolecule is about three times as large as ranibizu-mab and may remain in the eye longer and,therefore, possibly allow for less frequent injections.In clinical practice, however, the same dosing andfollow-up criteria are often applied for both drugs.

Whether or not these treatment modalities aremodifiable can only be decided after appropriatetrials have generated reliable data.

Given the inadequate safety data, the widespreadoff-label use of bevacizumab is not justified inclinical practice. On the other hand, a majorchallenge in the management of patients whorequire repeated anti-VEGF injections is the highcost of ranibizumab. This may lead to a situation inwhich patients are denied anti-VEGF therapy if off-label bevacizumab is not used. This dilemmaunderlines the need for head-to-head studies com-paring both VEGF antibodies, or, at least, wellcontrolled randomized trials evaluating intravitrealbevacizumab.

The conditions that have led to the failure togenerate such data have been observed before.There are several examples of interventions thatcreep into medical practice and achieve acceptancethey do not deserve on the basis of underlyingevidence.4 On the other side, the whole communityabstains from initiating state-of-the-art head-to-headtrials. Instead, critical assessment has been replacedby a belief supported only by case series substitutedfor high-quality trials.

The current situation is particularly complexbecause the distributors of both drugs, Novartis(Lucentis) and Roche (Avastin), and the manufac-turer, Genentech, are not economically indepen-dent and, thus, have not shown any interest infunding such trials. Therefore, pharmaceuticalindustry independent head-to-head studies suchas the IVAN study in Great Britain,A the CATT studyin the USA,B the EQUAL study in the Netherlands,C

the MANTA study in Austria,D and the VIBERAstudy in GermanyE are in progress. First results areexpected by the end of 2010. These trials investigateoutcomes such as efficacy, safety, quality of life,variations in treatment modalities and costs ofbevacizumab in comparison to ranibizumab. In themeantime, patients and doctors should be aware ofthe insufficient safety data regarding intravitrealbevacizumab.

References

1. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitrealbevacizumab for treatment of neovascular age-relatedmacular degeneration: a one-year prospective study. Am JOphthalmol. 2008;145:249--56

2. Bashshur ZF, Schakal A, Hamam RN, et al. Intravitrealbevacizumab vs verteporfin photodynamic therapy for neo-vascular age-related macular degeneration. Arch Ophthal-mol. 2007;125:1357--61

3. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versusverteporfin for neovascular age-related macular degeneration.N Engl J Med. 2006;355:1432--44

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4. Edwards P, Arango M, Balica L, et al. Final results of MRCCRASH, a randomised placebo-controlled trial of intrave-nous corticosteroid in adults with head injury-outcomes at 6months. Lancet. 2005;365:1957--9

5. Falkenstein IA, Cheng L, Morrison VL, et al. Standardizedvisual acuity results associated with primary versus secondarybevacizumab (Avastin) treatment for choroidal neovascula-rization in age-related macular degeneration. Retina. 2007;27:701--6

6. Fung AE, Rosenfeld PJ, Reichel E. The internationalintravitreal bevacizumab safety survey: using the internet toassess drug safety worldwide. Br J Ophthalmol. 2006;90:1344--9

7. Geitzenauer W, Michels S, Prager F, et al. Early effects ofsystemic and intravitreal bevacizumab (Avastin) therapy forneovascular age-related macular degeneration. Klin Mon-atsbl Augenheilkd. 2006;223:822--7

8. Hahn R, Sacu S, Michels S, et al. Intravitreal bevacizumabversus verteporfin and intravitreal triamcinolone acetonidein patients with neovascular age-related macular degener-eation. Ophthalmologe. 2007;104:588--93

9. Lazic R, Gabric N. Intravitreally administered bevacizumab(Avastin) in minimally classic and occult choroidalneovascularization secondary to age-related macular degen-eration. Graefes Arch Clin Exp Ophthalmol. 2007;245:68--73

10. Lazic R, Gabric N, Dekaris I, et al. Intravitreal bevacizu-mab (Avastin) in treatment of neovascular age-relatedmacular degeneration. Coll Antropol. 2007;31(Suppl 1):S315--9

11. Lazic R, Gabric N. Verteporfin therapy and intravitrealbevacizumab combined and alone in choroidal neovascula-rization due to age-related macular degeneration. Ophthal-mology. 2007;114:1179--85

12. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab forneovascular age-related macular degeneration. N Engl JMed. 2006;355:1419--31

13. Sacu S, Michels S, Prager F, et al. Randomised clinical trial ofintravitreal Avastin vs photodynamic therapy and intravitrealtriamcinolone: long-terms results. Eye.1--5

14. Steinbrook R. The price of sight—ranibizumab, bevacizu-mab, and the treatment of macular degeneration. N Engl JMed. 2006;355:1409--12

15. Weigert G, Michels S, Sacu S, et al. Intravitreal bevacizu-mab (Avastin) therapy versus photodynamic therapy plusintravitreal triamcinolone for neovascular age-relatedmacular degeneration: 6-month results of a prospective,randomised, controlled clinical study. Br J Ophthalmol.2008;92:356--60

16. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al.Twelve-month safety of intravitreal injections of bevacizu-mab (Avastin): results of the Pan-American CollaborativeRetina Study Group (PACORES). Graefes Arch Clin ExpOphthalmol. 2008;246:81--7

Other Cited Material

A. IVAN Study. www.controlled-trials.com. ISRCTN92166560.Accessed July 30, 2009

B. CATT Study. www.clinicaltrials.gov. NCT00593450. AccessedJuly 30, 2009

C. EQUAL Study. www.who.int/trialsearch.de. NTR1331. AccessedJuly 30, 2009

D. Manta Study. www.clinicaltrials.gov. NCT00710229. AccessedJuly 30, 2009

E. VIBERA Study. www.clinicaltrials.gov. NCT00559715. AccessedJuly 30, 2009

The authors reported no proprietary or commercial interest inany product mentioned or concept discussed in this article. Thework was supported by a grant of the German health insurancecompanies.

Reprint address: Christine Schmucker, PhD, German CochraneCenter, Institute of Medical Biometry and Medical Informatics,Department of Medical Biometry and Statistics, UniversityMedical Center Freiburg, Stefan-Meier-Str. 26, 79104 Freiburg,Germany. e-mail: [email protected].