Appendix B: Overview of the Drug Development Process

Drug development is a lengthy and uncertain process. The discovery, development, and testing of a new compound can last over a decade from initial concept to widespread clinical use, and is rife with potential for failure. A number of drugs currently in development for HCV may not succeed in demonstrating efficacy, or may show unacceptably high levels of toxicity. In some cases, the development of antiviral agents is halted or delayed due to financial considerations. Pharmaceutical companies may opt to terminate a development program that seems unlikely to result in a product generating sufficient revenue, while small biotechs may be unable to raise the financing necessary to support large clinical trials. Promising compounds identified by government or academic research may never find a commercial sponsor to conduct the preclinical and clinical research necessary for approval. Despite these odds, the outlook for new HCV therapeutics remains encouraging, with a pipeline of compounds at various stages of development.

Drug development can be roughly divided into three stages: drug discovery, preclinical development, and clinical development. New drugs are only tested in humans during the clinical development stage.

Drug Discovery
This stage of research focuses on identifying compounds that may be active against HCV. Several processes may be involved:

• Target validation: confirming that the target—for example, a particular site on the HCV NS3 serine protease—is appropriate for developing inhibitory strategies;
• Screening assay development: establishing in vitro models suitable for testing potential compounds for activity against a target (i.e., that a compound can inhibit NS3 serine protease activity);
• Lead identification: selecting a candidate compound for further preclinical development;
• Lead optimization: examining and potentially improving on the physical and chemical properties of the lead compound with respect to areas that can include potency, toxicity, and pharmacology (drug bioavailability—adsorption, distribution, metabolism, and excretion).

Researchers have a number of methods to pursue these processes, including high throughput screening of compound libraries and structure-based design. Pharmaceutical companies have vast libraries of compounds potentially active against a given target. Automated high throughput screening techniques can rapidly and efficiently identify lead compounds. Rational or structure-based drug design attempts to produce molecules with antiviral potential based on the three-dimensional structure of the target. In HCV drug discovery, the determination of crystal structures of the HCV serine protease, RNA-dependent RNA polymerase, and helicase enzymes has enabled the design of molecules that can bind to active sites on these enzymes. A host of related compounds with similar targets can be synthesized through combinatorial chemistry techniques, which tweak the chemical structure of a compound to improve its antiviral and pharmacologic properties. All of these methods have been applied to HCV research, identifying and generating lead compounds for targets such as the HCV NS3 serine protease and HCV RNA strand synthesis.

Preclinical Development
Pharmacology and toxicity studies of lead compounds are extended in the preclinical phase to in vitro studies and animal models, prior to human testing in the clinical development stage. In vitro models, such as HCV replicons, can help to characterize the antiviral activity of a lead compound. Other in vitro systems can help to predict the specificity, toxicity, and pharmacologic profile of a lead compound. Chimpanzees remain the only established animal model for HCV infection, and therefore the best in vivo model for drug efficacy prior to human trials. Some recent work has explored the value of mouse models, tamarin hepatocytes, and GB virus B-infected marmosets in validating the antiviral activity of new compounds.

Other animals not susceptible to HCV infection can be used to study the pharmacokinetics (how the body processes a drug) and pharmacodynamics (how a drug affects the body) of a compound. These studies help to establish potential dosing ranges and frequencies, and can define the relative value of different formulations (oral, infusion, etc.) of a compound. Manufacturing processes with appropriate quality control procedures are also developed during this stage. Animal research can also define the safety issues surrounding a drug candidate, and some drug development efforts are halted at this stage due to unacceptable toxicity in animals. Toxicity can arise for various reasons, but particularly when a compound is not highly selective against its target—for instance, if the compound also acts against cellular proteins in a potentially harmful way.

Clinical Development
When an agent's sponsor (the pharmaceutical company) has compiled all of the necessary preclinical data, particularly on safety, they can submit an investigational new drug application (IND) to the FDA outlining plans for safety and efficacy testing in humans. If approved, research advances in phases. Development can be halted at any phase if study results are unfavorable due to high toxicity and/or poor efficacy, poor pharmacologic properties, or other negative safety data emerges from additional animal studies. Clinical development programs can also be stalled or terminated due to economic factors and business decisions.

• Phase I: Small studies of healthy volunteers or, in some cases, individuals with stable HCV infection that determine short-term safety, explore dosing, and determine pharmacokinetics in humans. Phase I trials are not designed to establish the efficacy of a drug, though some information on the drug's activity may be collected. Phase I studies enroll up to a few dozen participants and can be conducted within a year's time.
• Phase II: Medium-sized trials examining longer-term safety and efficacy in the target population—i.e., individuals with chronic HCV infection. Some aspects of phase I and II trials may be combined and are used to identify the optimal dose of the drug. Phase II studies may enroll up a few hundred participants and can last for up to two years. The majority of development failures for compounds that have entered human studies occur during this phase.
• Phase III: Longer, large-scale randomized clinical trials determining safety and efficacy. These studies can enroll hundreds to thousands of participants and may last for several years. Phase III research is designed to prove that a drug works and is relatively safe, by comparing it to standard of care or placebo. FDA approval is contingent on the results of these trials.
• Phase IV: Post-marketing studies conducted after a drug's approval by the FDA. Intended to gather data about long-term or rare toxicities, and may collect information about the use and efficacy of the drug in various patient groups.

The discovery, preclinical, and clinical stages of drug development increasingly overlap. Companies also increasingly describe their clinical trials by dividing early phases into loosely (and often, inconsistently) defined subcategories. Phase Ia may be used to describe initial tests in healthy (e.g., uninfected) volunteers, while phase Ib sometimes refers to early short-term tests in people with HCV. Phase IIa studies compare the pharmacokinetics of various doses for longer periods, and phase IIb studies may generate initial data about the use of a new agent in combination (e.g., with interferon).

Many drugs that are currently in early (phase I and II) clinical development may not reach the market for several years. Compounds currently in preclinical development may not become available until the next decade. These timetables have particular relevance to people with hepatitis C and their doctors who are currently considering whether to treat now with pegylated interferon/ribavirin, or defer treatment until better drugs become available.

The development of a prophylactic vaccine could take even longer. Even if a strong candidate vaccine was entering clinical trials, testing for efficacy—the ability of the vaccine to prevent new HCV infections—could take several years and thousands of subjects. A preventative vaccine must be tested in uninfected persons, with an endpoint of whether people receiving the vaccine are less likely to develop infection than people who do not receive the vaccine. The amount of people necessary to test vaccine efficacy depends on the rate of new infections in a population; a high-risk population (such as injection drug users) with a high annual incidence of new HCV infections would be a logical group for vaccine efficacy trials. But even among injection drug users, not everyone will become infected with HCV in a given period of time, regardless of whether they receive the vaccine under investigation. Also, ethics dictate that vaccine trial participants receive information, counseling, and tools to reduce their risk of HCV infection—for example, information on the risk of needle-sharing and referral to a syringe exchange program or drug treatment. If people participating in a vaccine trial reduce their overall risk of HCV infection as a result of these interventions, sample size and/or duration of observation will necessarily increase.

For both drug and vaccine development, Phase III trials are enormously costly undertakings, and general require the direct involvement or financing by a large and established pharmaceutical company. Frequently cited (albeit controversial) estimates of the total cost of developing a new drug from discovery through to FDA approval exceed 800 million (Rawlins 2004). The necessary resources and, to varying degrees, expertise involved in clinical testing and drug approval often exceed the capacities of smaller, start-up biotech firms, which typically operate for several years without substantial revenue until their first products reach the market. As a result, the numerous biotechs with candidate HCV compounds generally have to form partnerships with larger pharmaceuticals to raise the capital for phase II and III clinical trials.

Many biotechs have particular expertise in a specialized field of drug development (e.g., compound screening; design of prodrugs), and pharmaceutical companies often enter into partnerships with them aimed at HCV drug discovery and lead identification. Companies may also enter partnerships with academic research groups, and compounds and techniques identified through academic research are commonly licensed to industry or spun off into new biotechs.

Many of these partnerships and discovery programs are referenced in Chapter X (The Future of HCV Therapy) to provide a glimpse at the scope and extent of HCV research. However, the history of drug development suggests that few of these discovery and preclinical research programs will result in new drugs reaching the market. According to current estimates, only an estimated one in 5,000-10,000 compounds evaluated in initial screening during the discovery and preclinical stages will reach the market. Based on industry averages, only one in three compounds being evaluated in clinical trials will ultimately receive FDA approval (Preziosi 2004).