Special Report: Inside the AED Development Process
The therapeutic role of generic antiepileptic drugs (AEDs) has been an area of intense research and debate. Data suggest that concerns about the safety and efficacy of generic AEDs may be well founded. For example, one analysis of patients with a diagnosis of epilepsy who had an epileptic event requiring acute care found these individuals were 80 percent more likely to have had a recent AED substitution than were matched controls without an acute event.1 Another analysis showed that generic AED use was associated with significantly greater medical utilization and risk of epilepsy-related medical events compared to branded drug use.2 Despite a significant number of similar research findings, the issue of substitution remains controversial, and the practice remains widespread.
Those who favor generic substitution point to the lower purchase cost of generics relative to innovator drugs. Much of the difference in costs owes to the different research and development paths that bring these agents to market.
Developing a Novel AED
The development of a novel, branded AED is a timeconsuming and expensive process. According to James Zackheim, PhD, CNS Medical Director for UCB (maker of Keppra [levetiracetam] and Vimpat [lacosamide]), bringing a novel agent to market represents the culmination of years of laboratory and clinical research, peppered with false starts and disappointments. The costs associated with laboratory and clinical research are significant, whether a compound progresses through preliminary investigation phases only or through to human trials and approval. And the research costs continue to mount once an agent comes to market, when companies sponsor ongoing data-gathering through initiatives such as pregnancy registries.
The AED development process begins in the laboratory with the identification of molecular compounds that may fill unmet needs of patients with epilepsy, Dr. Zackheim says. From any number of promising compounds, a handful may progress to animal testing aimed at determining their potential efficacy in human disease. Even at this early stage, Dr. Zackheim says, researchers are also looking at issues like side effects, including liver toxicity, and potential drug interactions.
Increasingly, Dr. Zackheim says, computer models are helping predict which molecules show the greatest clinical potential, and are supporting the design of optimal human clinical trials. The models are useful tools that are beneficial in the development process, but they can’t replace the type of knowledge and information gathered through human trials. “The ultimate level of sophistication and detail [in computer models] is not so great that we can know for certain how a molecule will perform in clinical use,” Dr. Zackheim says. He notes that reasonably establishing the safety and benefit of a drug requires “thousands of patient-years of exposure and years and years of experience.” Theoretical models provide more accurate predictions in the early stages of development, he says, but they become less reliable at predicting clinical outcomes in the “real world.”
Designing clinical trials requires a careful balancing of ethical and practical considerations, Dr. Zackheim says. He notes that drug developers must weigh the investment of time and finances against the likely benefit of the compound for patients with epilepsy. Furthermore, they must show that the agent has a distinct method of action and will therefore benefit patients.
Currently, AEDs that come to market are indicated for add-on therapy. That indication results from the nature of clinical trials; it would be clearly unethical to relegate control patients with epilepsy to no treatment (placebo only), and questionably ethical to provide other patients a treatment that lacks a substantial body of human data to support its efficacy. A benefit of testing new molecules as add-ons, Dr. Zackheim points out, is that it helps demonstrate that the investigational agent provides a different mechanism of action than the therapy to which it was added. Single-use indications for AEDs are not likely to emerge in the near future.* [Please see clarification below.] “I’d be surprised if there is a change in the clinical or regulatory pathway for epilepsy drugs,” Dr. Zackheim says.
Post-market Research and Generic Challengers
Once an innovator drug gains approval from the FDA, sponsored research continues. There may be trials aimed at developing or gaining clearance for alternative dosage forms, and there will be data collection for both general safety and pregnancy outcomes. The use of AEDs by pregnant women is an area of intense scrutiny. In the initial period after a drug earns FDA approval, its likely effect on the pregnant patient and developing fetus are judged based on animal models. Lacosamide, for example, is rated category C. A “C” rating indicates that adequate controlled studies in pregnant humans are lacking, and data from animal studies are either inconclusive or suggest a risk to the fetus; benefit in pregnant humans may outweigh risks. Data from pregnancy registries may support the use of particular AEDs during pregnancy or identify those agents that ought to be avoided.
Clearly, branded AEDs undergo an extensive and costly development program that provides physicians a great deal of data that allows them to predict the effects of the drug in certain populations. FDAapproved drugs are patented, and patent exclusivity generally lasts seven years. After that time, generic formulations may come to market after a less comprehensive and much less expensive development process.
Proponents and opponents of generic substitution both point to the FDA approval process to support their claims about the benefit or detriment of generics. As most clinicians know, FDA requires that a generic formulation demonstrate bioequivalence—often assessed in healthy volunteers—to an innovator formulation. Essentially, that means that the bioavailability of the generic, which must feature the same active ingredient in the same dosage form (caplet, oral solution, injection, IV, etc.) but will differ in excipients, must not differ significantly (more than 20 percent) from the innovator. If the formulation meets the bioequivalence standard, it is assumed to provide similar benefit to the innovator without being studied in a sample of patients with disease. Development of a generic challenger is by no means inexpensive, but it represents a fraction of the cost of developing an innovator. This difference in costs accounts for the 50 to 70 percent lower purchase price for generics compared to brand name drugs.
A report released last year by UnitedHealth Group says that use of generic drugs across the American healthcare system has saved $734 billion over the last decade. Patients save from $20 to $60 per prescription when switching from brands to generics. Healthcare reform efforts are likely to further drive the generic market, already estimated to be a $90 billion industry.
Lower prescription costs may not tell the whole story, though. Studies detail higher healthcare utilization costs associated with generic substitution of AEDs;3,4 highest costs were seen when patients were switched between multiple generic formulations.4 Other studies show substantially higher switch-back rates for AEDs—up to 20 percent—compared to antihyperlipidemics and antidepressants.5 Loss of seizure control or excessive side effects are among assumed drivers of switch-back.
The development of a novel antiepileptic drug is a complex and multifaceted process, with which few clinicians and fewer patients have extensive knowledge. Gaining familiarity with the process and the unique challenges of bringing a new agent to market may help clinicians recognize the role of specific AEDs in patient care and contribute to a better understanding of the also complex and multifaceted issue of generic formulations.
While the adjunctive therapy indication remains the most common route for initial FDA approval of an AED, formulations may subsequently pursue a single-use indication. Several AEDs have received approval for single-use indications, and, in fact, clinical trials are currently underway to ascertain the efficacy of lacosamide monotherapy.
Of note, recent publications in Epilepsia (online June 18, 2010; www.epilepsia.com) address the appropriate design of trials to demonstrate the efficacy of AED monotherapy.