by Associate Professor Ian Yeo Yew San
Guest editor for APBN August issue
Physicians are constantly inundated with new clinical trials purporting benefits of a new therapy or treatment regime. Consider the treatment of exudative age related macular degeneration (AMD) with anti-vascular endothelial growth factors (anti-VEGF), for example. Numerous clinical trials including ANCHOR1, MARINA2, CATT3, VIEW4 and many more have promised visual gains of 7-8 letters. Yet when we study real life data of patients receiving this treatment outside of clinical trials, such treatment outcomes do not hold up. The SEVEN-UP study5 and the CATT 5 year outcomes6 demonstrate clearly that visual gains could not be maintained over the long term outside of a clinical trial setting. In the real life clinical setting, the application of evidence-based medicine is often met with frustration. Why is this so?
Frequently, randomized controlled trials are designed to be explanatory trials. The major aim of an explanatory trial is to demonstrate the greatest benefit while minimizing resources spent on the trial. To maximize the chance of demonstrating a beneficial biological effect, patient cohorts involved in such clinical trials are often highly selected and homogenous. A major limitation of such explanatory clinical trials is, therefore, the inability to generalize results to the wider population. Consider then, the majority of patients we encounter in the “real world” will not conform to the inclusion and exclusion criteria imposed by the clinical trials that we base our management decisions upon. That Fovista, an anti platelet derived growth factor (anti-PDGF), poised to shatter the therapeutic ceiling of anti-VEGF treatment from its Phase II results7, but failed spectacularly in the Phase III trial with a more heterogeneous study population, is a sobering reminder of how important generalizability is when evaluating therapies.
Patients that agree to enter a clinical trial are inherently different from those that do not. Besides the obvious exclusion of patients with co-morbid conditions that may predispose to poorer outcomes, patients with low mobility, poor compliance to follow up/treatment or those with poor insight into their disease may be self-excluded. Often, the patients that need treatment most, such as those with poor vision, failed previous treatment, or have recurrent disease, are not the same patients that have participated in these trials and will likely not achieve the same outcomes. Trial protocols and results should be applied cautiously in these patients to avoid overtreatment and disappointment.
Clinical trials as well do not take into account the difficulty of implementing the same kind of rigorous follow up schedule and treatment regimen in the real world. The controlled environment of a clinical trial simply cannot be replicated in a real life clinical setting with limited resources. Similarly, clinical trials cannot replicate the effects of treatment fatigue and compliance issues that are common in the real world. A missed appointment, a patient (or physician) discouraged by less than satisfactory visual improvement, a longer wait at the clinic than is tolerable or treatment phobia from a painful injection all conspire to lower the real world efficacy of treatment.
In summary, clinical trials inform clinical practice and are a cornerstone of evidence-based medicine (EBM) but real world data demonstrates that EBM is but one component of the complex landscape of medicine that we practice. The best treatment outcomes can only be achieved by a combination of clinical experience, rational application of trial results and an enduring patient-doctor relationship. This is something that we as clinicians must remember and certainly help guide our next generation of clinicians as they navigate through the ever-growing maze of publications.
- Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. The New England journal of medicine. Oct 05 2006;355(14):1432-1444.
- Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. The New England journal of medicine. Oct 05 2006;355(14):1419-1431.
- Comparison of Age-related Macular Degeneration Treatments Trials Research G, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. Jul 2012;119(7):1388-1398.
- Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. Dec 2012;119(12):2537-2548.
- Bhisitkul RB, Mendes TS, Rofagha S, et al. Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON studies: the SEVEN-UP study. American journal of ophthalmology. May 2015;159(5):915-924 e912.
- Comparison of Age-related Macular Degeneration Treatments Trials Research G, Maguire MG, Martin DF, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. Aug 2016;123(8):1751-1761.
- Jaffe GJ, Ciulla TA, Ciardella AP, et al. Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled Trial. Ophthalmology. Feb 2017;124(2):224-234.
About the Author
Assoc Prof Ian Yeo Yew San
Deputy Medical Director (Education)
Head, Medical Retina Dept
Singapore National Eye Centre
Academic Vice-Chair (Education)
Ophthalmology and Visual Sciences Academic Clinical Programme
SingHealth & Duke-NUS Medical School, Singapore
Assoc Professor Yeo obtained his Medical Degree from the National University of Singapore in 1992. He did Ophthalmology residency training in Singapore. He obtained his post-graduate Ophthalmology qualifications in 1999 and completed a further 3 years of advance surgical training. He obtained his specialist accreditation in 2003 and started to pursue a Vitreo Retina subspecialty training at the Singapore National Eye Centre under Prof Ang Chong Lye. In 2006, he was awarded a HMDP grant to further his vitreo retinal training in Sydney, Australia under Drs Andrew Chang and Paul Beaumont. He is currently the Deputy Medical Director (Education) and a senior consultant vitreo retinal surgeon managing both medical and surgical retina conditions at the Singapore National Eye Centre. He is also an Academic Vice Chair (Education) and Director, Professional and Post undergraduate Education of the Academic Clinical Program for Ophthalmology at SingHealth / Duke-NUS Graduate School of Medicine and a clinical lecturer with the NUS-YLL medical school.
Assoc Professor Yeo has research interest include age related macular degeneration(AMD) and polypoidal choroidal vasculopathy (PCV), two very important blinding conditons in Singapore. He has engaged in primate work developing animal models for AMD and looked at novel new strategies for delivering drugs for the condition under the retina. SNEC has collaborated with the Genomic Institute of Singapore to study the genetics of AMD and PCV. He is also a Principal Investigator for a number of international clinical trials for these 2 conditions.
His other research interests include retinovascular condtions including diabetic retinopathy. He is actively involved in clinical trials for these conditions as a co-investigator.
Assoc Prof Ian Yeo Yew San, MBBS, MMED, MCI, FRCS is a Consultant, Cornea Service, SNEC and Asst. Professor at DUKE University - NUS. He has currently more than 90 peer-reviewed publications (H-index=21), majority of which are first or corresponding author with JIF>2.0, focusing on translational research, such as corneal transplantation studying prognostic factors to improve outcomes. He has published a few book chapters, including one in the prestigious CORNEA. He has filed for several patents for ophthalmic devices and awarded several national grants to study cornea imaging and innovation. His research work has also been recognized by international awards and is a regular invited speaker at international conferences. He is a Clinical Lecturer at the National University of Singapore School of Medicine, teaching and mentoring undergraduates, post-graduates, and Residents. He has several past and present leadership positions, including Chair of the Ophthalmology Pharmacy & Therapeutics at the Singapore National Eye Center and he has just graduated from the Leadership Development Program at the Asia Pacific Academy of Ophthalmology. He is also heavily committed to charity work in the Ophthalmology field, running community projects with the Singapore Society of Ophthalmology. As Director of Global Clinic (www.global-clinic.org), he regularly organizes missions and travels to provide free cataract surgery in countries such as Indonesia, Thailand, Cambodia, India and Myanmar.