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The Development of New Drugs for Ophthalmology
PERSPECTIVES The Development of New Drugs for Ophthalmology Gary D. Novack, Ph.D. near the estimate provided by DiMasi and asso ciates, 2 the incremental cost of ophthalmic de velopment was probably much less. As more drugs are targeted for ophthalmic use first, rather than for systemic use, costs of develop ment are no longer incremental, but approach the large sums discussed for systemic drugs. Examples of these drugs used for ophthalmic indications first, rather than later, include the topical carbonic anhydrase inhibitors and anticataract drugs. Drug development is usually sponsored by for-profit pharmaceutical firms. While there is
Drug development is a special application of the scientific method. In the scientific method, one generates a testable hypothesis, conducts an experiment, and then either rejects or fails to reject the hypothesis. One then conducts addi tional experiments on the basis of the outcome of the first experiment. The key feature of the scientific method is a testable hypothesis. If there is no hypothesis (that is, only data gather ing), or the hypothesis is not testable, then it is not considered scientific research. In drug de velopment, the testable hypotheses relate to the efficacy and safety of the drug. The time and expense involved in developing new drugs is substantial. Accounting for the cost of research and development on a product basis is complex. It is difficult to assign costs to basic research (for example, how does the cili ary body produce aqueous humor) vs specific drugs (for example, evaluating Drug A as a suppressor of aqueous production). 1 The con siderable task of estimating these costs was undertaken by DiMasi and associates. 2 Working with confidential data supplied by pharmaceu tical firms for all medical specialties, they cal culated that the interval and cost involved from chemical synthesis to marketing approval (Fig ure) average 12 years and $114 million (1987 dollars), respectively. Capitalizing this out-ofpocket expense to the point of marketing ap proval at a 9% discount rate yields an average cost estimate of $231 million. 2 Unfortunately, it is not possible at this time to gather from their data development costs and timing for the sub set of ophthalmic drugs.
Direct Research Cost « l i e M;ii:„n„l Concept for therapy
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Tile NewDrug ADDUCIition NDA Review and approval
Many drugs used in ophthalmology were originally developed for the treatment of sys temic disease, with their ophthalmic uses being found subsequently. To decrease business risks and development time, some ophthalmic phar maceutical companies have licensed from an other company the ophthalmic rights to their systemic drugs. Examples include ciprofloxacin, flurbiprofen, levobunolol, metipranolol, and fluorometholone. Although sys temic development of these drugs was probably
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Figure (Novack). The drug development process. Timing and direct research cost is provided on the basis of my experience. Additional developmental costs, not displayed, may include chemistry and man ufacturing expenses, capital equipment and facilities, administrative and management time, insurance, and the cost of funds. Ellipses indicate no upper limit. 357
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an opportunity for profit for the investors, there is also a great risk. Approximately 99.9% of compounds synthesized do not become reve nue-producing products for the company be cause of inadequate efficacy, unacceptable toxicity, or other reasons. The key in the scientific method of drug development is to ask the question (that is, experiment early in the devel opment process), before resources are expend ed unnecessarily. For example, if the goal is to develop a longer-acting pilocarpine, then the duration of the ocular hypotensive action of the new agent relative to that of conventional pilo carpine is the most important experiment. If a more comfortable anti-inflammatory agent is the goal, then an early experiment should com pare the new agent to a currently marketed one. Discovery and development of drugs is a sequential process (Figure). A new therapeutic agent frequently begins as a theoretical modi fication of a physiologic process. Examples include the antagonism of the chronotropic effects of catecholamines (propranolol), 3 or antagonism of carbonic anhydrase in the ciliary body (acetazolamide). 4 In such cases, the body's own agonist or enzyme substrate is the chemical starting point for a series of analogues (Figure). Various chemical analogues are next synthe sized, and evaluated in in vitro and in vivo models for this disease. The biologic model need not be an exact model of the disease, but merely a model for the disease. That is, the model's sensitivity and specificity with respect to existing clinical therapies is more important than whether the animal disease is actually similar to the human disease. 5 For example, ß-adrenoceptor antagonists, although not very effective as ocular hypotensive agents in nor mal rabbits, can antagonize the ocular hypoten sive effects of isoproterenol. This action of the ß-adrenoceptor antagonist, which is actually a hypertensive effect, can be used to evaluate new agents for intraocular ß-adrenoceptor blockade in a relatively inexpensive model. 6 The next step is pharmaceutical formulation, which begins with an evaluation of the mole cule's stability and solubility. An ideal drug candidate has the optimal physicochemical properties to enable it to cross the corneal barrier readily. The most preferred delivery system for ophthalmic agents is an aqueous eyedrop. A drug may be insoluble in water, necessitating a micronized suspension. Thus, pharmaceutical scientists are challenged to de velop aqueous formulations in which the drug
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remains stable for a product shelf life of at least two years at controlled room temperature (15 to 30 C). Multidose containers require protection against microbial contamination; thus, a pre servative that is compatible with the drug and not irritating to the eye must be added. The pH and buffering of the formulation must not lead to discomfort, and the viscosity must not inter fere with instillation or visual transparency. Some drugs are inherently discomforting, and acceptance can be provided only by decreasing the concentration of the active molecule in the final formulation. The next step in drug development is toxicol ogy. Also known as safety evaluation, this step involves exposing several species of animals to increasingly larger doses and durations of treatment with the test compound. This contin uum begins with short-term studies (one dose up to several instillations per day), continues with intermediate-term studies (up to one month), and finally long-term studies (six to 12 months). These studies evaluate any changes in animal health or behavior, as well as extensive gross and microscopic pathologic characteris tics. Acute and subacute studies are generally required before testing of the new drug in humans. The commitment of resources for long-term studies is generally not made until there are some positive data from the shortterm human trials. Drugs intended for longterm use also may require in vitro evaluation of their mutagenicity, and in vivo evaluation of their potential for eliciting birth defects (teratogenicity) and cancer (carcinogenicity). At this point, the company evaluates the biologic evidence for activity, its potency for efficacy relative to its potency for toxicity, and the suitability of the compound for acceptable formulations. If these criteria are met, and there still is a large projected therapeutic need for this type of compound, then the firm proposes clinical evaluation. A regulatory submission is required in most countries to administer an investigational drug to humans. In the United States, this regulatory submission is called an Investigational New Drug Application. This submission includes reports from the biologic, toxicologie, and pharmaceutic studies, the pro posed clinical plan and indication for use, and the chemistry and pharmaceutics to demon strate a stable, known product. In practice, a firm generally confers with the Food and Drug Administration before submitting an Investiga tional New Drug Application to assure that the early development plan will provide sufficient
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data, and be of limited risk to volunteers and patients. Ophthalmic drugs are currently re viewed by the Food and Drug Administration's Division of Medical Imaging, Surgical, and Dental Drug Products. Technically, the Investigational New Drug Application is a notification to the Food and Drug Administration that, if no contrary word is heard, the company will begin the proposed clinical studies in approximately 30 days. The filing of an Investigational New Drug Application, and its status, is confiden tial, unless released by the firm. Therefore, it is not possible to state accurately the number of drugs under active clinical investigation for ophthalmic indications, or their developmental status. Clinical research studies are divided into four major phases (Phases I through IV). Phase I studies are intended primarily to evaluate the safety and pharmacokinetics of the new drug in normal volunteers. These studies start with low doses for brief periods of administration (one drop, for example), and continue through more extended concentrations, frequencies, and du rations. The objective is to monitor the safety of the product while slowly increasing the expo sure (dose, frequency, or duration) to the vol unteer. The comfort of the formulation is often assessed at this time.7"91 know of several poten tial products that were found unacceptable at this stage—either because of discomfort of a new vehicle, or discomfort of a combination of two agents that were comfortable given sepa rately, but not together. In the United States today, it is important to know the systemic exposure of ocularly instilled drugs. It is dur ing Phase I that many firms choose to eval uate plasma levels of the topically applied drug. 10 Only approximately one third of all drugs entering Phase I evaluation make it to Phase HI evaluation. 2 A drug clears Phase I evaluations with negative data; that is, the absence of notable ocular or systemic toxicity at intended therapeutic doses. The patent posi tion on the proprietary nature of the new drug may not be clear at this time. For these reasons, few Phase I studies are submitted for publica tion. As toxicology on the drug's potential teratogenicity is generally not complete at this time, the inclusion of women of child-bearing potential in these studies is restricted. If the drug is indicated for a relatively rare disease (less than 200,000 patients/year, for example), then a firm may consider applying for an orphan designation. Granting of this desig nation provides tax and marketing exclusivity
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incentives, as well as the potential for publicity. An orphan drug must still be evaluated in the various phases of clinical investigation, but smaller patient numbers are generally required as, by definition, less patients are available for study. 11 All clinical evaluations should be conducted by an independent investigator in studies de signed to minimize bias. When possible, this involves masking the study medications, and the use of positive and negative controls. 12 For example, if one is evaluating the mydriatic potential of a new drug, one should attempt to include both a mydriatic (cyclopentolate, for example) as a positive control and the vehicle of the new drug as a negative control. When it is difficult to mask the investigator from the treat ment (with laser or surgical procedures, for example), one may consider using an inde pendent observer to make critical measure ments. 13 Any proprietary relationship of the clinical investigator with the product being evaluated should be disclosed. Phase II studies also use dosage escalation regimens similar to those of Phase I, but in patients with the intended disease, rather than in normal volunteers. Phase II studies include dose-response, time-response evaluations. 14 · 15 Early Phase II studies are generally placebocontrolled, as absolute efficacy is the first ques tion.16·17 If enhanced efficacy or safety over ex isting therapy is a sine qua non for the putative product, then Phase II studies may incorporate active controls. It is only after the completion of a Phase II trial that the pharmaceutical compa ny gets human efficacy data for their com pound. The interval from demonstration of effi cacy in animal studies until receipt of results from Phase II studies may be up to several years, and cost several million dollars. First results of efficacy studies in the medical litera ture or at meetings are usually based on a pilot Phase II study. Examples of ophthalmic drugs for which further development was stopped after Phase II include metoprolol (too short acting) 18 and di-acetyl-nadolol (blepharoconjunctivitis). 19 Once there is demonstration of efficacy in patients, there are many ethical, financial, sci entific, and political pressures to proceed rapid ly toward the next step, Phase III trials. Howev er, investigation as to the selection of the appropriate concentration and frequency of use should be a key segment of Phase II investiga tions. Many clinical pharmacologists in indus try, government, and academia believe that in
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hastening Phase III trials, one fails to optimize the dose. With oral therapy in systemic medi cine, the dose may be modified by administer ing two pills rather than one or by cutting a pill in half. In ophthalmology, a dose cannot realis tically be modified by instilling a second drop, or instilling one half of a drop. Many of our marketed drugs are available in only one or two concentrations, so that only the frequency of use can be modified. If only one concentration can be selected for further development, a high er concentration is usually favored over a lower concentration to maximize efficacy, although there might be greater potential safety with the lower concentration. This tendency to select dosing that represents the "plateau" phase of the dose-response curve is probably reasonable for drugs with large therapeutic indices (for example, antibiotics), but probably worthy of further exploration for drugs with narrower therapeutic indices (for example, autonomie drugs and corticosteroids).
any device used. One must define what change, if observed consistently, would constitute a meaningful difference. Both the firm that de signs the studies and the Food and Drug Ad ministration reviewers must agree on the divid ing line for differences that are meaningful. For the recently approved ophthalmic quinolone antibiotics, a clinically significant difference was a 20% difference in cure rates between the quinolone and the standard therapy (tobramycin or gentamicin). This required approximate ly 80 to 100 patients who met all protocol requirements per treatment group. However, because only 42% of patients who entered with clinical bacterial infections met the rigorous culture requirements, 22 approximately 450 pa tients per trial, or 900 Phase III patients were required. For a recently approved topical antiinflammatory drug, a clinically significant difference was 0.5 to 1.0 grades in anterior chamber cells (0 to 3 scale). This required ap proximately 100 patients per group per study. 25
Phase HI studies are extended trials (up to one year of dosing per patient) in large pa tient populations (generally 100 to 1,000) that use the concentration, formulation, and dos ing regimens of the intended marketed pro duct.20'23 Both safety and efficacy are measured in Phase III. For most drugs, at least two Phase HI trials are required to provide substantive evidence of efficacy and safety. As with all clinical trials, the cost of Phase III trials in cludes the physician's time for examining and treating the patient, laboratory tests, inpatient stays, the study medications, and study man agement and data handling. As at least two Phase III trials must be conducted that must include large numbers of patients for long treatment periods, this is the most expensive phase of drug development, with costs ranging from hundreds of thousands to millions of dollars. The logistics of administering these large studies often exceed the ability of the pharmaceutical company's staff, and so inde pendent private research organizations some times are employed to assist in the trial man agement. An example of an ophthalmic drug rejected after Phase III trials is oral sorbinil for diabetic retinopathy, which was rejected be cause of inadequate efficacy.24
Several years ago, some researchers had pro posed a decrease in intraocular pressure of 4 mm Hg as a clinically significant difference in ocular hypotensive therapies. This means that the difference in reducing intraocular pressure between the two drugs would be, at most, 4 mm Hg. From today's perspective, that difference was too liberal, as the ocular hypotensive effica cy of several agents was found equivalent to that of timolol within 4 mm Hg, but not within 2 mm Hg. For recently approved ocular hypo tensive agents, a clinically significant differ ence was judged as 2 mm Hg.'This required approximately 30 to 50 patients per group per trial. An even more rigorous standard, such as 1 mm Hg, is debatable. At this time, I know of no agent with an ocular hypotensive efficacy that would be found equivalent within 2 mm Hg, but not within 1 mm Hg. A clinician probably would not judge two agents that differed by only 1 mm Hg in their ocular hypotensive efficacy to be clinically different. If this more rigorous standard was selected, it would re quire a doubling of the sample size (and there fore costs and time) to reach this standard. Equivalency standards can also be set for safety measures. However, even with the dimensions of Phase HI trials, only relatively frequent ad verse experiences (that is, incidence of 1% or greater) are expected to be detected, and differ ences in safety between agents are difficult to detect.
An important definition in comparative trials of efficacy and safety is the clinically significant difference. Any measurement in a patient is confounded by inherent variability among pa tients, the pathologic condition, drug manufac ture, compliance, and the measurement error of
In designing a Phase III trial, the standards for regulatory review several years in the future
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must be predicted. For example, antiglaucoma drugs have been approved to date on the basis of their ocular hypotensive efficacy. Increased intraocular pressure carries with it an increased risk of further progressive loss of visual field.2627 Also monitored in studies for approved drugs were visual field (either by manual Goldmann or automated threshold techniques) and cup/disk ratio (by direct ophthalmoscopy). There is a large peer-reviewed literature on the influence of accepted glaucoma therapies on these measures. We know what the standard therapies do to these measures, and how to interpret statistically significant differences vis a-vis their clinical relevance. 28 There are many developing procedures for the measurement of ocular disease, including new visual field tests,29,3" stereoacuity, 31 retinal nerve fiber layer photography, 32 - 33 and measures of color vision function.31·34·35 In the future, these measures of visual function may become standards of care in evaluating the effect of glaucoma therapy. However, to my knowledge, such tests are not yet fully validated as to their ability to measure the efficacy of glaucoma therapy. Validation would come from controlled clinical trials as well as clinical experience in how meaningful such measures are in diagnosis and therapy. One would hesitate to risk the time and re sources of a Phase III trial that uses investigational measurement systems to evaluate investigational agents. Another decision in study design is the cross over vs parallel comparison. In a crossover study, each patient receives each treatment in a separate period. In a parallel study, patients are randomly assigned to receive only one of the treatments. Crossover studies require fewer pa tients than parallel studies, and have the inher ent appeal of using each patient as their own control. However, in a crossover study, all pa tients have to complete all periods, there can be no unequal carryover of treatment effect from one period to the next, and the disease must remain stable. 36 Because ß-adrenoceptor antag onists have effects for at least two weeks, 37 a crossover trial is probably not the best study design for evaluating these types of agents. Patients generally underdose both in number of doses and in interval between doses.38,39 This would tend to underestimate both efficacy and toxicity of a drug, and complicate the evalua tion of a new therapy. An objective measure of compliance would be preferred so that the rela tionship of lack of efficacy or side effects to underdosing or overdosing could be analyzed.
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Although there are commercially available de vices to monitor compliance with oral medica tion regimens, 40 none is currently available for ophthalmic medication. If the agent proves effective, relatively safe, and has the intended characteristics (safer than current therapy, or greater efficacy or longer duration of action, for example), then the firm requests marketing approval from the Food and Drug Administration. This request, called a New Drug Application in the United States, is a large submission (up to 150 volumes) that re quires the integration of the extensive clinical program (which may involve millions of pieces of data). Each piece of clinical data must have been checked from its source (generally a case report form) through its various electronic ma nipulations. A minimum of several months are involved in this data quality check and the subsequent rigorous statistical analysis. The New Drug Application must include the toxi cology, chemistry, manufacturing, and controls data. The firm must have demonstrated that the product can be manufactured at a site that meets the rigorous demands of quality control and repeatability. As mentioned previously, many drugs have already been approved for systemic use before the submission of the New Drug Application for the ophthalmic indication (norfloxacin, for example). The experience with the systemic use of the drug provides a larger knowledge base for the Food and Drug Administration in their review of the possible risks associated with the drug. The review of New Drug Applications for all specialties by the Food and Drug Adminis tration averages from one to three years over the past three decades. 41 There are examples of short review times in ophthalmology (apraclonidine was reviewed in less than three months, for example). However, the review time for most recently approved ophthalmic drugs falls into the previously mentioned range. The re view is generally an interactive process, in which the Food and Drug Administration may ask for clarification, reanalysis, additional stud ies, or revisions to the proposed indications. On approval of the New Drug Application, the company may sell the drug as prescribed by physicians. Not all ophthalmic drugs and their indica tions have approved New Drug Applications at the Food and Drug Administration. Drugs in troduced before 1962 such as pilocarpine, epinephrine, or oral fluorescein are not approved, but their use is acceptable in standard practice.
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Still other d r u g s are a p p r o v e d for o n e indica tion, b u t p r e s c r i b e d for a n o t h e r . For e x a m p l e , as yet, n o topical n o n c o r t i c o s t e r o i d a l a n t i - i n flammatory d r u g is a p p r o v e d in t h e U n i t e d States for the t r e a t m e n t of cystoid m a c u l a r e d e m a . These a g e n t s may be p r e s c r i b e d for this indication by a n o p h t h a l m o l o g i s t , b u t a firm may n o t p r o m o t e their d r u g for this u n a p p r o v e d claim. Recently, the Food a n d D r u g A d m i n i s t r a tion h a s taken a s t r o n g line a g a i n s t p r o m o t i o n for u n a p p r o v e d i n d i c a t i o n s . P h a s e IV s t u d i e s are c o n d u c t e d e i t h e r d u r i n g the review p e r i o d , or after a p p r o v a l . T h e s e studies may be for e x t e n d e d indications 4 2 ( a d d i tional d o s a g e r e g i m e n s or d i s e a s e s , for e x a m ple), or e x t e n d e d h u m a n e x p e r i e n c e for safety e v a l u a t i o n in larger p a t i e n t p o p u l a t i o n s in m o r e realistic use ( p o s t m a r k e t s u r v e i l l a n c e , for example). 4 3 45 In this p h a s e , t h e u s e of o n e a g e n t w h e n u s e d in c o m b i n a t i o n w i t h a n o t h e r m a r keted p r o d u c t may b e further e v a l u a t e d . In my experience in this area, the initial N e w D r u g A p p l i c a t i o n for l e v o b u n o l o l w a s for t h e 0 . 5 % s t r e n g t h f o r m u l a t i o n for o n c e - a n d t w i c e - d a i l y use, w i t h b o t h p l a c e b o - a n d t i m o l o l - c o n t r o l l e d s t u d i e s . D u r i n g the a p p r o x i m a t e l y t w o - y e a r r e view p e r i o d , a n d in t h e e n s u i n g y e a r s , P h a s e IV studies w e r e c o n d u c t e d o n t h e u s e of t h e 0 . 2 5 % - s t r e n g t h f o r m u l a t i o n of l e v o b u n o l o l , w i t h b o t h o n c e - a n d twice-daily a d m i n i s t r a tion, for i n t r a o c u l a r p r e s s u r e i n c r e a s e s after laser or cataract surgical p r o c e d u r e s , a n d in c o m p a r i s o n to o t h e r m a r k e t e d a g e n t s s u c h as betaxolol a n d metipranolol. 4 6 ' 5 0 S u p p l e m e n t s to the N e w D r u g A p p l i c a t i o n h a v e so far r e s u l t e d in a p p r o v a l for 0 . 2 5 % l e v o b u n o l o l w i t h a t w i c e daily a d m i n i s t r a t i o n . Many of our n e w t h e r a p i e s in o p h t h a l m o l o g y will come from the d e v e l o p m e n t of c o m p o u n d s as s p o n s o r e d b y private p h a r m a c e u t i c a l firms. This p r o c e s s is long, risky, a n d r e q u i r e s rigor ous controls in scientific p r o c e d u r e s , i n t e r p r e tation, a n d quality c o n t r o l . This o v e r v i e w of the d r u g d e v e l o p m e n t p r o c e s s e m p h a s i z e d t h e clin ical i n v e s t i g a t i o n p h a s e s . With the synergistic c o o p e r a t i o n of basic a n d clinical scientists, clin ical investigators, a n d our c o l l e a g u e s in p h a r m a c e u t i c s a n d r e g u l a t o r y affairs, w e can c o n t i n u e to p r o v i d e n e w t h e r a p i e s for p a t i e n t s .
From Pharma«Logic Development, Inc., and Universi ty of California, Irvine, California. This study was pre sented in part at the combined American Glaucoma Society/Annual North American Glaucomatologists Learning Ensemble meeting in Coronado, California, Dec. 14, 1991.
Reprint requests to Gary D. Novack, Ph.D., Pharma»Logic Development, Inc., 46 Ashwood, Irvine, CA 92714.
References 1. Vagelos, P. R.: Are prescription drug prices high? Science 252:1080, 1991. 2. DiMasi, J. A., Hansen, R. W., Grabowski, H. G., and Lasagna, L.: Cost of innovation in the pharma ceutical industry. J. Health Econ. 10:107, 1991. 3. Black, J.: Drugs from emasculated hormones. The principle of syntopic antagonism. Science 245:486, 1989. 4. Kupfer, C , Gaasterland, D., and Ross, K.: Stud ies of aqueous humor dynamics in man. V. Effects of acetazolamide and isoproterenol in young and old normal volunteers. Invest. Ophthalmol. 15:349, 1976. 5. Novack, G. D., and Zwolshen, J. M.: Predictive value of muscle relaxant models in rats and cats. J. Pharmacol. Methods 10:175, 1983. 6. Woodward, D. F., Chen, J., Padillo, E., and Ruiz, G.: Pharmacological characterization of ß-adrenoceptor subtype involvement in the ocular hypoten sive response to ß-adrenergic stimulation. Exp. Eye Res. 43:61, 1986. 7. Novack, G. D., Lue, J. C , and Duzman, E.: Pow er estimates for glaucoma trials. Clin. Pharmacol. Ther. 41:208, 1987. 8. Weisweiler, P. S., Barnett, P. S., Chen, K. S., Kelley, E. P., and Novack, G. D.: Comparative com fort of flurbiprofen solution and indomethacin sus pension eyedrops. J. Clin. Res. Drug Develop. 2:233, 1988. 9. Scoville, B., Krieglstein, G. K., Then, E., Yokoyama, S., and Yokoyama, T.: Measuring drug-in duced eye irritation. A simple new clinical assay. J. Clin. Pharmacol. 25:210, 1985. 10. Novack, G. D., Tang-Liu, D., Glavinos, E. P., Liu, S., and Shen, D.: Plasma levels following topical administration of levobunolol. Ophthalmologica 194:194, 1987. 11. Haffner, M. E.: Orphan products. Origins, progress, and prospects. Ann. Rev. Pharmacol. Toxicol. 31:603, 1991. 12. Smith, E. B.: Effect of investigator bias on clini cal trials. Arch. Dermatol. 125:216, 1989. 13. The Glaucoma Laser Trial Group: The Glau coma Laser Trial (GLT). 2. Results of argon laser trabeculoplasty versus topical medicines. The Glau coma Laser Trial Research Group. Ophthalmology 97:1403, 1990. 14. Repass, R., Eto, C. Y., Lee, P. H., and Sinclair, L.: An evaluation of the duration of action and safety of PilaSite in ocular hypertensive patients. ARVÓ abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1991, p. 946. 15. Vogel, R., Sheeden, A., Laurence, J. K., and Neafus, R.: The ocular hypotensive effect of once
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daily administration of timolol-in-gelrite (TG) versus timolol solution (TS). ARVO abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1991, p. 942. 16. Bensinger, R., Keates, E., Gofman, J., Novack, G. D., and Duzman, E.: Levobunolol. A three month efficacy study in the treatment of glaucoma and ocular hypertension. Arch. Ophthalmol. 103:375, 1985. 17. Feghali, J. G., and Kaufman, P. L.: Decreased intraocular pressure in the hypertensive human eye with betaxolol, a beta-1-adrenergic antagonist. Am. J. Ophthalmol. 100:777, 1985. 18. Ros, F. E., Dake, C. L., Nagelkerke, N. J. D., and Greve, E. L.: Metoprolol eye drops in the treat ment of glaucoma. A double-blind single-dose trial of a beta-1-adrenergic blocking drug. Albert von Graefes Arch. Klin. Ophthalmol. 206:247, 1978. 19. Duzman, E., Rosen, N., and Lazar, M.: Diacetyl nadolol. 3-month ocular hypotensive effect in glaucomatous eyes. Br. J. Ophthalmol. 67:668, 1983. 20. Caldwell, D. R., Hartwich-Young, R., and Drake, M.: Efficacy and safety evaluation of lodoxamide 0.1% ophthalmic solution versus cromolyn sodi um 4% ophthalmic solution in patients with vernal keratoconjunctivitis (VKC). ARVO abstracts. Supple ment to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1991, p. 736. 21. Levobunolol Study Group: Levobunolol. A four-year study of efficacy and safety in glaucoma treatment. Ophthalmology 96:642, 1989. 22. Leibowitz, H. M.: Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the treatment of bacterial conjunctivitis. Am. J. Ophthal mol. 112(suppl.):29S, 1991. 23. Brown, R. H., Stewart, R. H., Lynch, M. G., Crandall, A. S., Mandell, A. I., Wilensky, J. T., Schwartz, A. L., Gaasterland, D. E., DeFaller, J. M., and Higginbotham, E. J.: AL02145 reduces the intra ocular pressure elevation after anterior segment laser surgery. Ophthalmology 95:378, 1988. 24. Sorbinil Retinopathy Trial Research Group: A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy. Arch. Ophthalmol. 108:1234, 1990. 25. Vickers, F. F., McGuigan, L. J. B., Ford, C , Wysowskyj, H., Meilars, K., Koester, ]., and Ahmed, M.: The effect of diclofenac sodium ophthalmic on the treatment of postoperative inflammation. ARVO abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1991, p. 793. 26. Sommer, A.: Intraocular pressure and glauco ma. Am. J. Ophthalmol. 107:186, 1989. 27. David, R., Zangwill, L., Stone, D., and Yassur, Y.: Epidemiology of intraocular pressure in a popula tion screened for glaucoma. Br. J. Ophthalmol. 71:766, 1987. 28. Werner, E. B., Petrig, B., Krupin, T., and Bish op, K. I.: Variability of automated visual fields in clinically stable glaucoma patients. Invest. Ophthal mol. Vis. Sci. 30:1083, 1989. 29. Lachenmayr, B. J., Drance, S. M., Douglas,
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G. R., and Mikelberg, F. S.: Light-sense, flicker and resolution perimetry in glaucoma. A compara tive study. Graefes Arch. Clin. Exp. Ophthalmol. 229:246, 1991. 30. House, P., Schulzer, M., Drance, S., and Doug las, G.: Characteristics of the normal central visual field measured with resolution perimetry. Graefes Arch. Clin. Exp. Ophthalmol. 229:8, 1991. 31. Bassi, C. J., and Galanis, J. C : Binocular visual impairment in glaucoma. Ophthalmology 98:1406, 1991. 32. Sommer, A., Katz, J., Quigley, H. A., Miller, N. R., Robin, A. L., Richter, R. C , and Witt, K. A.: Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch. Ophthalmol 109:77, 1991. 33. Sommer, A., Quigley, H. A., Robin, A. L., Mill er, N. R., Katz, J., and Arkell, S.: Evaluation of nerve fiber layer assessment. Arch. Ophthalmol. 102:1766, 1984. 34. Yu, T. C , Falcao-Reis, F., Spileers, W., and Arden, G. B.: Peripheral color contrast. A new screening test for preglaucomatous visual loss. In vest. Ophthalmol. Vis. Sci. 32:2779, 1991. 35. Motolko, M., Drance, S. M., and Douglas, G. R.: The early psychophysical disturbances in chronic open-angle glaucoma. A study of visual func tions with asymmetric disc cupping. Arch. Ophthal mol. 100:1632, 1982. 36. Fleiss, J. L.: The Design and Analysis of Clini cal Experiments. New York, John Wiley and Sons, 1986, p. 263. 37. Schlecht, L. P., and Brubaker, R. F.: The effects of withdrawal of timolol in chronically treated glau coma patients. Ophthalmology 95:1212, 1988. 38. Kass, M. A., Meltzer, D. W., Gordon, M., Coo per, D., and Goldberg, J.: Compliance with topical pilocarpine treatment. Am. J. Ophthalmol. 101:515, 1986. 39. Kass, M. A., Gordon, M„ Morley, R. E., Melt zer, D. W., and Goldberg, J. J.: Compliance with topical timolol treatment. Am. J. Ophthalmol. 103:188, 1987. 40. Engstrom, F. W., and Urquhart, J.: Electronic monitoring of medication compliance in depressed outpatients. Clin. Pharmacol. Ther. 45:159, 1989. 41. DiMasi, J. A., Bryant, N. R., and Lasagna, L.: New drug development in the United States from 1963 to 1990. Clin. Pharmacol. Ther. 50:471, 1991. 42. Spivey, R. N., Lasagna, L., and Trimble, A. G.: New indications for already-approved drugs. Time trends for the new drug application review phase. Clin. Pharmacol. Ther. 41:368, 1987. 43. Novack, G. D., Eto, C. Y., Lue, J. C , and Branin, M.-J.: A post-marketing evaluation of levo bunolol, a topical ophthalmic drug. J. Clin. Res. Drug Develop. 1:197, 1987. 44. Novack, G. D., Kelley, E. P., and Lue, J. C : A multicenter evaluation of levobunolol (VISTAGAN) in Germany. Ophthalmologica 197:90, 1988. 45. Schnarr, K.-D.: Vergleichende multizentrische Untersuchung von carteolol-augentropfen mit an-
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deren betablockern bei 768 patienten unter alltagsbedingungen. Klin. Monatsbl. Augenheilkd. 192:167, 1988. 46. Long, D. A., Johns, G. E., Mullen, R. S., Bowe, R. G., Alexander, D., Epstein, D. L., Weiss, M. J., Masi, R. } . , Charap, A. D., Eto, C. Y., and Novack, G. D.: Levobunolol and betaxolol. A double-masked controlled comparison of efficacy and safety in pa tients with elevated intraocular pressure. Ophthal mology 95:735, 1988. 47. Silverstone, D. E., Novack, G. D., Kelley, E. P., and Chen, K. S.: Prophylactic treatment of intraocular pressure elevations after neodymium:YAG laser posterior capsulotomies and extracapsular cataract extractions with levobunolol. Ophthal mology 95:713, 1988.
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48. Silverstone, D., Zimmerman, T., Choplin, N., Mundorf, T., Rose, A., Stoecker, J., Kelley, E., arid Lue, J.: Evaluation of once-daily levobunolol 0.25% and timolol 0.25% for increased intraocular pres sure. Am. J. Ophthalmol. 112:56, 1991. 49. Krieglstein, G. K., Novack, G. D., Voepel, E., Schwarzbach, G., Schunck, K. P., Lue, J. C., and Glavinos, E. P.: Levobunolol and metipranolol. Comparative ocular hypotensive efficacy, safety and comfort. Br. J. Ophthalmol. 71:250, 1987. 50. Ober, M., Scharrer, A., Novack, G. D., and Lue, J. C : Die lokale subjektive Vertraglich keit von Levobunolol und Metipranolol in einer DoppelblinkVergliechsstudie bie Patienten mit erhöhtem intraokularem druck. Ophthalmologica 192:159, 1986.
Drug development is a special application of the scientific method. In the scientific method, one generates a testable hypothesis, conducts an experiment, and then either rejects or fails to reject the hypothesis. One then conducts addi tional experiments on the basis of the outcome of the first experiment. The key feature of the scientific method is a testable hypothesis. If there is no hypothesis (that is, only data gather ing), or the hypothesis is not testable, then it is not considered scientific research. In drug de velopment, the testable hypotheses relate to the efficacy and safety of the drug. The time and expense involved in developing new drugs is substantial. Accounting for the cost of research and development on a product basis is complex. It is difficult to assign costs to basic research (for example, how does the cili ary body produce aqueous humor) vs specific drugs (for example, evaluating Drug A as a suppressor of aqueous production). 1 The con siderable task of estimating these costs was undertaken by DiMasi and associates. 2 Working with confidential data supplied by pharmaceu tical firms for all medical specialties, they cal culated that the interval and cost involved from chemical synthesis to marketing approval (Fig ure) average 12 years and $114 million (1987 dollars), respectively. Capitalizing this out-ofpocket expense to the point of marketing ap proval at a 9% discount rate yields an average cost estimate of $231 million. 2 Unfortunately, it is not possible at this time to gather from their data development costs and timing for the sub set of ophthalmic drugs.
Direct Research Cost « l i e M;ii:„n„l Concept for therapy
* Synthesize chemical analogs 1
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6 60
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3 36
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Phase III (Efficacy and safety) 1
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Tile NewDrug ADDUCIition NDA Review and approval
Many drugs used in ophthalmology were originally developed for the treatment of sys temic disease, with their ophthalmic uses being found subsequently. To decrease business risks and development time, some ophthalmic phar maceutical companies have licensed from an other company the ophthalmic rights to their systemic drugs. Examples include ciprofloxacin, flurbiprofen, levobunolol, metipranolol, and fluorometholone. Although sys temic development of these drugs was probably
3
18
3 -30
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4
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Figure (Novack). The drug development process. Timing and direct research cost is provided on the basis of my experience. Additional developmental costs, not displayed, may include chemistry and man ufacturing expenses, capital equipment and facilities, administrative and management time, insurance, and the cost of funds. Ellipses indicate no upper limit. 357
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an opportunity for profit for the investors, there is also a great risk. Approximately 99.9% of compounds synthesized do not become reve nue-producing products for the company be cause of inadequate efficacy, unacceptable toxicity, or other reasons. The key in the scientific method of drug development is to ask the question (that is, experiment early in the devel opment process), before resources are expend ed unnecessarily. For example, if the goal is to develop a longer-acting pilocarpine, then the duration of the ocular hypotensive action of the new agent relative to that of conventional pilo carpine is the most important experiment. If a more comfortable anti-inflammatory agent is the goal, then an early experiment should com pare the new agent to a currently marketed one. Discovery and development of drugs is a sequential process (Figure). A new therapeutic agent frequently begins as a theoretical modi fication of a physiologic process. Examples include the antagonism of the chronotropic effects of catecholamines (propranolol), 3 or antagonism of carbonic anhydrase in the ciliary body (acetazolamide). 4 In such cases, the body's own agonist or enzyme substrate is the chemical starting point for a series of analogues (Figure). Various chemical analogues are next synthe sized, and evaluated in in vitro and in vivo models for this disease. The biologic model need not be an exact model of the disease, but merely a model for the disease. That is, the model's sensitivity and specificity with respect to existing clinical therapies is more important than whether the animal disease is actually similar to the human disease. 5 For example, ß-adrenoceptor antagonists, although not very effective as ocular hypotensive agents in nor mal rabbits, can antagonize the ocular hypoten sive effects of isoproterenol. This action of the ß-adrenoceptor antagonist, which is actually a hypertensive effect, can be used to evaluate new agents for intraocular ß-adrenoceptor blockade in a relatively inexpensive model. 6 The next step is pharmaceutical formulation, which begins with an evaluation of the mole cule's stability and solubility. An ideal drug candidate has the optimal physicochemical properties to enable it to cross the corneal barrier readily. The most preferred delivery system for ophthalmic agents is an aqueous eyedrop. A drug may be insoluble in water, necessitating a micronized suspension. Thus, pharmaceutical scientists are challenged to de velop aqueous formulations in which the drug
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remains stable for a product shelf life of at least two years at controlled room temperature (15 to 30 C). Multidose containers require protection against microbial contamination; thus, a pre servative that is compatible with the drug and not irritating to the eye must be added. The pH and buffering of the formulation must not lead to discomfort, and the viscosity must not inter fere with instillation or visual transparency. Some drugs are inherently discomforting, and acceptance can be provided only by decreasing the concentration of the active molecule in the final formulation. The next step in drug development is toxicol ogy. Also known as safety evaluation, this step involves exposing several species of animals to increasingly larger doses and durations of treatment with the test compound. This contin uum begins with short-term studies (one dose up to several instillations per day), continues with intermediate-term studies (up to one month), and finally long-term studies (six to 12 months). These studies evaluate any changes in animal health or behavior, as well as extensive gross and microscopic pathologic characteris tics. Acute and subacute studies are generally required before testing of the new drug in humans. The commitment of resources for long-term studies is generally not made until there are some positive data from the shortterm human trials. Drugs intended for longterm use also may require in vitro evaluation of their mutagenicity, and in vivo evaluation of their potential for eliciting birth defects (teratogenicity) and cancer (carcinogenicity). At this point, the company evaluates the biologic evidence for activity, its potency for efficacy relative to its potency for toxicity, and the suitability of the compound for acceptable formulations. If these criteria are met, and there still is a large projected therapeutic need for this type of compound, then the firm proposes clinical evaluation. A regulatory submission is required in most countries to administer an investigational drug to humans. In the United States, this regulatory submission is called an Investigational New Drug Application. This submission includes reports from the biologic, toxicologie, and pharmaceutic studies, the pro posed clinical plan and indication for use, and the chemistry and pharmaceutics to demon strate a stable, known product. In practice, a firm generally confers with the Food and Drug Administration before submitting an Investiga tional New Drug Application to assure that the early development plan will provide sufficient
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data, and be of limited risk to volunteers and patients. Ophthalmic drugs are currently re viewed by the Food and Drug Administration's Division of Medical Imaging, Surgical, and Dental Drug Products. Technically, the Investigational New Drug Application is a notification to the Food and Drug Administration that, if no contrary word is heard, the company will begin the proposed clinical studies in approximately 30 days. The filing of an Investigational New Drug Application, and its status, is confiden tial, unless released by the firm. Therefore, it is not possible to state accurately the number of drugs under active clinical investigation for ophthalmic indications, or their developmental status. Clinical research studies are divided into four major phases (Phases I through IV). Phase I studies are intended primarily to evaluate the safety and pharmacokinetics of the new drug in normal volunteers. These studies start with low doses for brief periods of administration (one drop, for example), and continue through more extended concentrations, frequencies, and du rations. The objective is to monitor the safety of the product while slowly increasing the expo sure (dose, frequency, or duration) to the vol unteer. The comfort of the formulation is often assessed at this time.7"91 know of several poten tial products that were found unacceptable at this stage—either because of discomfort of a new vehicle, or discomfort of a combination of two agents that were comfortable given sepa rately, but not together. In the United States today, it is important to know the systemic exposure of ocularly instilled drugs. It is dur ing Phase I that many firms choose to eval uate plasma levels of the topically applied drug. 10 Only approximately one third of all drugs entering Phase I evaluation make it to Phase HI evaluation. 2 A drug clears Phase I evaluations with negative data; that is, the absence of notable ocular or systemic toxicity at intended therapeutic doses. The patent posi tion on the proprietary nature of the new drug may not be clear at this time. For these reasons, few Phase I studies are submitted for publica tion. As toxicology on the drug's potential teratogenicity is generally not complete at this time, the inclusion of women of child-bearing potential in these studies is restricted. If the drug is indicated for a relatively rare disease (less than 200,000 patients/year, for example), then a firm may consider applying for an orphan designation. Granting of this desig nation provides tax and marketing exclusivity
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incentives, as well as the potential for publicity. An orphan drug must still be evaluated in the various phases of clinical investigation, but smaller patient numbers are generally required as, by definition, less patients are available for study. 11 All clinical evaluations should be conducted by an independent investigator in studies de signed to minimize bias. When possible, this involves masking the study medications, and the use of positive and negative controls. 12 For example, if one is evaluating the mydriatic potential of a new drug, one should attempt to include both a mydriatic (cyclopentolate, for example) as a positive control and the vehicle of the new drug as a negative control. When it is difficult to mask the investigator from the treat ment (with laser or surgical procedures, for example), one may consider using an inde pendent observer to make critical measure ments. 13 Any proprietary relationship of the clinical investigator with the product being evaluated should be disclosed. Phase II studies also use dosage escalation regimens similar to those of Phase I, but in patients with the intended disease, rather than in normal volunteers. Phase II studies include dose-response, time-response evaluations. 14 · 15 Early Phase II studies are generally placebocontrolled, as absolute efficacy is the first ques tion.16·17 If enhanced efficacy or safety over ex isting therapy is a sine qua non for the putative product, then Phase II studies may incorporate active controls. It is only after the completion of a Phase II trial that the pharmaceutical compa ny gets human efficacy data for their com pound. The interval from demonstration of effi cacy in animal studies until receipt of results from Phase II studies may be up to several years, and cost several million dollars. First results of efficacy studies in the medical litera ture or at meetings are usually based on a pilot Phase II study. Examples of ophthalmic drugs for which further development was stopped after Phase II include metoprolol (too short acting) 18 and di-acetyl-nadolol (blepharoconjunctivitis). 19 Once there is demonstration of efficacy in patients, there are many ethical, financial, sci entific, and political pressures to proceed rapid ly toward the next step, Phase III trials. Howev er, investigation as to the selection of the appropriate concentration and frequency of use should be a key segment of Phase II investiga tions. Many clinical pharmacologists in indus try, government, and academia believe that in
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hastening Phase III trials, one fails to optimize the dose. With oral therapy in systemic medi cine, the dose may be modified by administer ing two pills rather than one or by cutting a pill in half. In ophthalmology, a dose cannot realis tically be modified by instilling a second drop, or instilling one half of a drop. Many of our marketed drugs are available in only one or two concentrations, so that only the frequency of use can be modified. If only one concentration can be selected for further development, a high er concentration is usually favored over a lower concentration to maximize efficacy, although there might be greater potential safety with the lower concentration. This tendency to select dosing that represents the "plateau" phase of the dose-response curve is probably reasonable for drugs with large therapeutic indices (for example, antibiotics), but probably worthy of further exploration for drugs with narrower therapeutic indices (for example, autonomie drugs and corticosteroids).
any device used. One must define what change, if observed consistently, would constitute a meaningful difference. Both the firm that de signs the studies and the Food and Drug Ad ministration reviewers must agree on the divid ing line for differences that are meaningful. For the recently approved ophthalmic quinolone antibiotics, a clinically significant difference was a 20% difference in cure rates between the quinolone and the standard therapy (tobramycin or gentamicin). This required approximate ly 80 to 100 patients who met all protocol requirements per treatment group. However, because only 42% of patients who entered with clinical bacterial infections met the rigorous culture requirements, 22 approximately 450 pa tients per trial, or 900 Phase III patients were required. For a recently approved topical antiinflammatory drug, a clinically significant difference was 0.5 to 1.0 grades in anterior chamber cells (0 to 3 scale). This required ap proximately 100 patients per group per study. 25
Phase HI studies are extended trials (up to one year of dosing per patient) in large pa tient populations (generally 100 to 1,000) that use the concentration, formulation, and dos ing regimens of the intended marketed pro duct.20'23 Both safety and efficacy are measured in Phase III. For most drugs, at least two Phase HI trials are required to provide substantive evidence of efficacy and safety. As with all clinical trials, the cost of Phase III trials in cludes the physician's time for examining and treating the patient, laboratory tests, inpatient stays, the study medications, and study man agement and data handling. As at least two Phase III trials must be conducted that must include large numbers of patients for long treatment periods, this is the most expensive phase of drug development, with costs ranging from hundreds of thousands to millions of dollars. The logistics of administering these large studies often exceed the ability of the pharmaceutical company's staff, and so inde pendent private research organizations some times are employed to assist in the trial man agement. An example of an ophthalmic drug rejected after Phase III trials is oral sorbinil for diabetic retinopathy, which was rejected be cause of inadequate efficacy.24
Several years ago, some researchers had pro posed a decrease in intraocular pressure of 4 mm Hg as a clinically significant difference in ocular hypotensive therapies. This means that the difference in reducing intraocular pressure between the two drugs would be, at most, 4 mm Hg. From today's perspective, that difference was too liberal, as the ocular hypotensive effica cy of several agents was found equivalent to that of timolol within 4 mm Hg, but not within 2 mm Hg. For recently approved ocular hypo tensive agents, a clinically significant differ ence was judged as 2 mm Hg.'This required approximately 30 to 50 patients per group per trial. An even more rigorous standard, such as 1 mm Hg, is debatable. At this time, I know of no agent with an ocular hypotensive efficacy that would be found equivalent within 2 mm Hg, but not within 1 mm Hg. A clinician probably would not judge two agents that differed by only 1 mm Hg in their ocular hypotensive efficacy to be clinically different. If this more rigorous standard was selected, it would re quire a doubling of the sample size (and there fore costs and time) to reach this standard. Equivalency standards can also be set for safety measures. However, even with the dimensions of Phase HI trials, only relatively frequent ad verse experiences (that is, incidence of 1% or greater) are expected to be detected, and differ ences in safety between agents are difficult to detect.
An important definition in comparative trials of efficacy and safety is the clinically significant difference. Any measurement in a patient is confounded by inherent variability among pa tients, the pathologic condition, drug manufac ture, compliance, and the measurement error of
In designing a Phase III trial, the standards for regulatory review several years in the future
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must be predicted. For example, antiglaucoma drugs have been approved to date on the basis of their ocular hypotensive efficacy. Increased intraocular pressure carries with it an increased risk of further progressive loss of visual field.2627 Also monitored in studies for approved drugs were visual field (either by manual Goldmann or automated threshold techniques) and cup/disk ratio (by direct ophthalmoscopy). There is a large peer-reviewed literature on the influence of accepted glaucoma therapies on these measures. We know what the standard therapies do to these measures, and how to interpret statistically significant differences vis a-vis their clinical relevance. 28 There are many developing procedures for the measurement of ocular disease, including new visual field tests,29,3" stereoacuity, 31 retinal nerve fiber layer photography, 32 - 33 and measures of color vision function.31·34·35 In the future, these measures of visual function may become standards of care in evaluating the effect of glaucoma therapy. However, to my knowledge, such tests are not yet fully validated as to their ability to measure the efficacy of glaucoma therapy. Validation would come from controlled clinical trials as well as clinical experience in how meaningful such measures are in diagnosis and therapy. One would hesitate to risk the time and re sources of a Phase III trial that uses investigational measurement systems to evaluate investigational agents. Another decision in study design is the cross over vs parallel comparison. In a crossover study, each patient receives each treatment in a separate period. In a parallel study, patients are randomly assigned to receive only one of the treatments. Crossover studies require fewer pa tients than parallel studies, and have the inher ent appeal of using each patient as their own control. However, in a crossover study, all pa tients have to complete all periods, there can be no unequal carryover of treatment effect from one period to the next, and the disease must remain stable. 36 Because ß-adrenoceptor antag onists have effects for at least two weeks, 37 a crossover trial is probably not the best study design for evaluating these types of agents. Patients generally underdose both in number of doses and in interval between doses.38,39 This would tend to underestimate both efficacy and toxicity of a drug, and complicate the evalua tion of a new therapy. An objective measure of compliance would be preferred so that the rela tionship of lack of efficacy or side effects to underdosing or overdosing could be analyzed.
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Although there are commercially available de vices to monitor compliance with oral medica tion regimens, 40 none is currently available for ophthalmic medication. If the agent proves effective, relatively safe, and has the intended characteristics (safer than current therapy, or greater efficacy or longer duration of action, for example), then the firm requests marketing approval from the Food and Drug Administration. This request, called a New Drug Application in the United States, is a large submission (up to 150 volumes) that re quires the integration of the extensive clinical program (which may involve millions of pieces of data). Each piece of clinical data must have been checked from its source (generally a case report form) through its various electronic ma nipulations. A minimum of several months are involved in this data quality check and the subsequent rigorous statistical analysis. The New Drug Application must include the toxi cology, chemistry, manufacturing, and controls data. The firm must have demonstrated that the product can be manufactured at a site that meets the rigorous demands of quality control and repeatability. As mentioned previously, many drugs have already been approved for systemic use before the submission of the New Drug Application for the ophthalmic indication (norfloxacin, for example). The experience with the systemic use of the drug provides a larger knowledge base for the Food and Drug Administration in their review of the possible risks associated with the drug. The review of New Drug Applications for all specialties by the Food and Drug Adminis tration averages from one to three years over the past three decades. 41 There are examples of short review times in ophthalmology (apraclonidine was reviewed in less than three months, for example). However, the review time for most recently approved ophthalmic drugs falls into the previously mentioned range. The re view is generally an interactive process, in which the Food and Drug Administration may ask for clarification, reanalysis, additional stud ies, or revisions to the proposed indications. On approval of the New Drug Application, the company may sell the drug as prescribed by physicians. Not all ophthalmic drugs and their indica tions have approved New Drug Applications at the Food and Drug Administration. Drugs in troduced before 1962 such as pilocarpine, epinephrine, or oral fluorescein are not approved, but their use is acceptable in standard practice.
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Still other d r u g s are a p p r o v e d for o n e indica tion, b u t p r e s c r i b e d for a n o t h e r . For e x a m p l e , as yet, n o topical n o n c o r t i c o s t e r o i d a l a n t i - i n flammatory d r u g is a p p r o v e d in t h e U n i t e d States for the t r e a t m e n t of cystoid m a c u l a r e d e m a . These a g e n t s may be p r e s c r i b e d for this indication by a n o p h t h a l m o l o g i s t , b u t a firm may n o t p r o m o t e their d r u g for this u n a p p r o v e d claim. Recently, the Food a n d D r u g A d m i n i s t r a tion h a s taken a s t r o n g line a g a i n s t p r o m o t i o n for u n a p p r o v e d i n d i c a t i o n s . P h a s e IV s t u d i e s are c o n d u c t e d e i t h e r d u r i n g the review p e r i o d , or after a p p r o v a l . T h e s e studies may be for e x t e n d e d indications 4 2 ( a d d i tional d o s a g e r e g i m e n s or d i s e a s e s , for e x a m ple), or e x t e n d e d h u m a n e x p e r i e n c e for safety e v a l u a t i o n in larger p a t i e n t p o p u l a t i o n s in m o r e realistic use ( p o s t m a r k e t s u r v e i l l a n c e , for example). 4 3 45 In this p h a s e , t h e u s e of o n e a g e n t w h e n u s e d in c o m b i n a t i o n w i t h a n o t h e r m a r keted p r o d u c t may b e further e v a l u a t e d . In my experience in this area, the initial N e w D r u g A p p l i c a t i o n for l e v o b u n o l o l w a s for t h e 0 . 5 % s t r e n g t h f o r m u l a t i o n for o n c e - a n d t w i c e - d a i l y use, w i t h b o t h p l a c e b o - a n d t i m o l o l - c o n t r o l l e d s t u d i e s . D u r i n g the a p p r o x i m a t e l y t w o - y e a r r e view p e r i o d , a n d in t h e e n s u i n g y e a r s , P h a s e IV studies w e r e c o n d u c t e d o n t h e u s e of t h e 0 . 2 5 % - s t r e n g t h f o r m u l a t i o n of l e v o b u n o l o l , w i t h b o t h o n c e - a n d twice-daily a d m i n i s t r a tion, for i n t r a o c u l a r p r e s s u r e i n c r e a s e s after laser or cataract surgical p r o c e d u r e s , a n d in c o m p a r i s o n to o t h e r m a r k e t e d a g e n t s s u c h as betaxolol a n d metipranolol. 4 6 ' 5 0 S u p p l e m e n t s to the N e w D r u g A p p l i c a t i o n h a v e so far r e s u l t e d in a p p r o v a l for 0 . 2 5 % l e v o b u n o l o l w i t h a t w i c e daily a d m i n i s t r a t i o n . Many of our n e w t h e r a p i e s in o p h t h a l m o l o g y will come from the d e v e l o p m e n t of c o m p o u n d s as s p o n s o r e d b y private p h a r m a c e u t i c a l firms. This p r o c e s s is long, risky, a n d r e q u i r e s rigor ous controls in scientific p r o c e d u r e s , i n t e r p r e tation, a n d quality c o n t r o l . This o v e r v i e w of the d r u g d e v e l o p m e n t p r o c e s s e m p h a s i z e d t h e clin ical i n v e s t i g a t i o n p h a s e s . With the synergistic c o o p e r a t i o n of basic a n d clinical scientists, clin ical investigators, a n d our c o l l e a g u e s in p h a r m a c e u t i c s a n d r e g u l a t o r y affairs, w e can c o n t i n u e to p r o v i d e n e w t h e r a p i e s for p a t i e n t s .
From Pharma«Logic Development, Inc., and Universi ty of California, Irvine, California. This study was pre sented in part at the combined American Glaucoma Society/Annual North American Glaucomatologists Learning Ensemble meeting in Coronado, California, Dec. 14, 1991.
Reprint requests to Gary D. Novack, Ph.D., Pharma»Logic Development, Inc., 46 Ashwood, Irvine, CA 92714.
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