The Rigorous Process of Ophthalmic Drug Development
MARTIN B. WAX, MD
Healthcare budgets constitute a significant part of governmental spending. Therefore, governments around the world are therefore trying to contain costs with intense scrutiny by both the public and private sectors. As a consequence, the pharmaceutical industry faces considerable challenges, both politically and fiscally. It is within this climate that the discovery of new medicines must flourish.
Research and development of new drugs is costly, time-consuming, and highly risky. Drug companies spend an average of 12-15 years to discover and develop a new drug to ensure that it is safe and effective at an average cost that is estimated at $500-900 million. Only 5 in 5000 compounds that enter preclinical testing ßmake it to human testing and only 1 of these 5 tested in people is approved.
R&D PRODUCTIVITY HAS DECREASED
Despite enormous increases in spending on novel technologies over the past several years, R&D productivity has decreased for the past decade as measured either by the number of new drugs approved per dollar spent, or by the number of original Investigational New Drug (IND) applications received by the FDA from commercial sources per dollar spent.
An understanding of the discovery and development process can be helpful in trying to assess why a productivity gap exists (Figure). Typically, the initial efforts to identify a specific druggable target take 2-3 years. Once validated, traditional screening of chemistry libraries results in a "hit" compound to that target about a year later. The next phase consists of optimizing the chemistry of the molecule and is the brunt of the work done in pharmaceutical companies. Such medicinal chemistry work takes another 1-3 years. The late stage of the discovery process is focused on proof of concept testing in animals, detailed studies of bioavailability, systemic absorption, distribution and clearance, safety and toxicology, and takes another 1-2 years. Clinical studies culminate after an additional 3-7 years of testing in man before a drug finally makes it to market.
The productivity gap exists even though pharmaceutical companies have invested prodigious amounts in novel discovery technologies such as structure-based drug design, combinatorial chemistry, high-throughput screening (HTS) and genomics, all of which brought 20-100 fold improvements in throughput. One key reason drugs fail appears to be the inability of the traditional R&D process to accurately predict the safety and toxicology problems that comprise the major reasons many molecular entities fail to make it through the pipeline and subsequent approval process. Surprisingly, clinical efficacy is not the sole reason drugs fail. Rather, animal and human toxicology, as well as bioavailability factors, are equivalent or even slightly outweigh lack of efficacy as the main reason for compounds dropping out of the pipeline. Most of the costs of drug development are incurred further in the pipeline, and the vast majority of attrition occurs in full clinical development (phases 2b and 3).
Failures due to lack of efficacy and safety demonstrate the need for the development of more predictive animal models and, more importantly, the need to develop experimental medicine paradigms that are more predictive of clinical outcomes so as to carry out such proof-of-concept clinical trials much earlier in development. This is especially true in ophthalmic drug development. As we enter the next decad novel drugs for retinal therapy will emerge, increasing the need for better models to predict clinical success are of paramount importance. For example, the models widely used now to assess whether a drug can hinder or abolish retinal or choroidal neovascularization generally rely on either a rodent model of oxygen induced retinopathy to induce preretinal neovascularization, or a mouse model of laser induced choroidal neovascularization. Neither of these models accurately mimics the precise lesions of proliferative neovascularization that occurs in human AMD or diabetic retinopathy. However, they are useful for proof-of-concept studies even though they are not human models. Therefore, we can expect that our understanding of the strengths and weaknesses of the new generation of retinal drugs developed with the aid of animal models will be greatly refined as we gain experience with their performance in the clinic.
Other explanations for the productivity gap are that the industry is currently attacking diseases of great complexity or that the entry bar for new drugs is higher because they are often competing with the enhanced standard of care created by the latest "new" drugs that immediately preceeded them. This often leads to more demanding hurdles that need to be satisfied in order to gain approval by the regulatory authorities both here and abroad. The latter trend will almost certainly continue in light of the recent concern over the safety of widely prescribed selective non-steroidal anti-inflammatory agents in which the FDA has been criticized for failing to identify a substantive health risk of those drugs prior to approval.
EFFORTS IN OPHTHALMOLOGY HAVE INTENSIFIED
Despite these obstacles, the efforts of the pharmaceutical industry have intensified in ophthalmology in the past few years and show no sign of waning. This is largely due to the remarkable (possibly once-in-a-lifetime) opportunity to make new drugs to treat macular degeneration and diabetic retinopathy, which together afflict approximately 50 million people in the 3 largest pharmaceutical markets of the United States, Europe, and Japan. The alignment of good science, novel advances in drug delivery, and a large unmet medical need is an irresistible combination that has resulted in the commitment of many pharmaceutical companies to devote great resources to the field of ophthalmology despite the daunting hurdles and high failure rates that still plague the industry. These efforts appear to be paying off. An unprecedented number of compounds are now in human clinical trials for ophthalmological diseases that include glaucoma, dry eye, and allergy in addition to retinal disease.
The twentieth century has witnessed a dramatic increase in human life expectancy as a consequence of several factors including increased medical knowledge, improved technologies and surgical techniques, and better health care and public health. Equally important however, is the discovery of a plethora of drugs such as nonsteroidal anti-inflammatory drugs, antibiotics, statins, and numerous other such innovative and crucial medicines from the pharmaceutical industry. The opportunities that abound now in ophthalmological drug development are clearly among the most exciting in medicine and ensure that ocular health will continue to improve worldwide in the twenty-first century.
Better medicines for glaucoma, new treatments for dry eye, and antiproliferative therapies for angiogenesis are just some of the reasons to be excited about the deliverables that pharma will deliver to ophthalmologists over the next decade and beyond. When these new medicines are realized they will be, in many cases, truly sight saving or sight restoring. Such accomplishments make the efforts to surmount the intimidating hurdles of the drug discovery process highly worthwhile.
Dr. Wax is vice president of research and development for Alcon Laboratories, Inc., and a professor in the department of ophthalmology at the University of Texas Southwestern Medical School in Dallas.
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Figure. The drug development process is a lengthy and complicated process, taking many years to complete.