Pre-Clinical Drug Development
All drug development starts in the laboratory in the phase that is termed pre-clinical development. This process generally takes up to 6 years or longer. When considering drug development, researchers must consider several fundamental questions during the pre-clinical phase. These questions are especially crucial in an orphan disease like CF where the margin for error is much smaller than for more common diseases. First and foremost, investigators must determine whether there is an unmet need. Are there any therapies available that addresses a certain area of the disease? Are the available therapies insufficient either from an efficacy or safety standpoint? Of the currently approved drugs, are there limitations on availability to everyone, whether due to cost, lack of effectiveness or adverse reactions? Other questions that must be considered include: what aspect of the disease will be targeted? Will the drug have to be active in several organs or just one organ? Within an organ, what process will be targeted? For example, in the lungs, will the drug impact the basic defect, abnormal airway environment, mucus obstruction, chronic infection or exaggerated inflammation (Figure 1)? Is the target a cell, a receptor, or a molecule? Will the drug correct an abnormal protein structure like a CFTR corrector, decrease something produced in excess like a pro-inflammatory mediator, or increase something that is not produced or produced in relatively low concentrations like anti-inflammatory molecules or CFTR in people with two nonsense mutations?
In a complex target like airway inflammation where there are many triggers impacting dozens of molecular pathways that result in the increased production of pro-inflammatory molecules or decreased production of counter-regulatory molecules, it is often difficult to determine the most efficacious target that is also a safe target. These complexities have made developing new anti-inflammatory therapies for CF extremely difficult. Over the last 30 years, dozens of anti-inflammatory drugs being considered for CF have failed along the way during the various phases of drug development(8-10). One candidate drug was actually associated with increased pulmonary exacerbations, the opposite of the intended effect(11). The clinical trial of this investigational product provided a lesson that highlights the importance of having adequate pre-clinical safety data in a disease-relevant animal model(12). The past provides a cautionary tale for all future drug development, not just for anti-inflammatory drugs.
During the pre-clinical phase of drug development, the efficacy of an investigational product is typically demonstrated in both in vitro and in vivo models. During pre-clinical experiments, having the correct assay is the cornerstone. The ideal assay is simple, high-throughput, directly relevant to the intended therapeutic target, and has the ability to discriminate between more or less efficacious analogous molecules. The investigator must consider what outputs should be used to measure efficacy and safety and how those outputs might be adapted for use in a clinical trial. Toxicology studies in disease-relevant animal models are important in order to determine dose-limiting toxicities and establish initial dosages that are likely to be safe in human studies. These are required as a part of the regulatory process and are ultimately geared toward minimizing risk of untoward effects happening in human trials. For example, when studying anti-inflammatory drugs, an important determination is at what dose might an anti-inflammatory (the target effect) become an immunosuppressive (an untargeted and potentially deleterious effect)(13)? This points to the importance of studying anti-inflammatory drugs in a representative model system, e.g., a CF mouse model with an active infection similar to what might occur in the human CF airway, versus a dissimilar animal model, e.g., a sterile mouse model. Adequate safety must be established in animals before proceeding to clinical trials in humans. Pre-clinical safety studies should be conducted under good laboratory practice (GLP) guidelines, which is defined as “a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported ”(14).
The ultimate goal of the pre-clinical phase of drug development is to file an Investigational New Drug (IND) application with the FDA. The FDA’s primary objective in evaluating pre-IND research is to ensure the rights and safety of human subjects are being protected. During the pre-clinical phase, several molecules in the same drug class may be under investigation, but eventually, a single lead compound, typically with a similar, backup compound, must be selected. Prior to the selection of the lead molecule, various modifications are considered to optimize activity and chemical properties to help ensure that the sponsor has the ability to make enough of the investigational product under good manufacturing practice (GMP) guidelines to complete all of the non-clinical safety tests. Under these guidelines, the production of an investigational compound must be consistently of high quality between batches. In the pre-clinical phase, animal studies provide information regarding the pharmacology and toxicology of the molecule under consideration. Animal studies also provide a basis for conducting a clinical trial. Typically, animal studies consist of a rodent species and a large non-rodent species. Once short-term toxicology data are available, a clinical trial can start, but human studies cannot be longer in duration than the duration of animal toxicology studies. For therapies intended for chronic use, six-month animal toxicology data are necessary for registration of the drug. The purpose of the animal studies is to provide information on a dose range or therapeutic window, initial dosages, an estimation of the risk:benefit ratio for humans, identification of target organ toxicities and safety margin, and identification of surrogate markers to monitor during clinical trials(15). At this point, an IND application is submitted to the FDA prior to proceeding to a clinical trial (Box 1). Once the FDA approves an IND, the investigator is able to proceed to human trials.
No overview of the pre-clinical phase of drug development would be complete without some discussion of funding. It is during the pre-clinical phase that collaborations between academic and industry colleagues are often forged. Prior to this point, academicians often secure research funding for pre-clinical studies from government agencies such as the NIH or private foundations such as the Cystic Fibrosis Foundation, amongst other sources. However, for development to proceed, academicians often must seek out industry collaborators. Industry sponsors must determine whether the area of research aligns with their priorities and whether the benefits of developing a new therapy in a specific disease area outweighs the costs and risks. Occasionally, a biotech firm may spinout from a university and the investigator who owns the intellectual property. These companies often support nascent projects through angel funding, which is start-up funding provided by an individual or a group of individual investors in return for equity in the company. The hope is to develop a candidate drug to the point that the company becomes an attractive investment for venture capitalists. Occasionally, these small biotech firms become cash strapped as drug development proceeds and angel funding begins to dwindle before the company becomes an attractive investment option for venture capitalists. Intellectual property (i.e., the drug in development) is often sold to a larger, more financially viable company; otherwise, development may stop. The Cystic Fibrosis Foundation has tried to bridge the gap between angel funding and venture capitalism through a process known as venture philanthropy. In this process, the CF Foundation supports drug development in return for equity in the sponsor/drug. The CF Foundation has in turn reinvested equity in development programs for other candidate drugs.
There are other mechanisms to encourage industry sponsors to work in CF, including financial benefits conferred by the Orphan Drug Act of 1983. The Orphan Drug Act recognizes that small populations of patients make it difficult for companies to profit from developing drugs for those diseases. The Orphan Drug Act provides benefits that include tax incentives, enhanced patent protections and marketing rights for seven years after approval, clinical research subsidies in the form of grants, FDA support for protocol development and study design, and waiving of Prescription Drug User Act filing fees. In addition, many drugs can be granted fast track status from the FDA if they are developed for rare pediatric diseases like CF. Fast track status will reduce the costs for sponsors and shorten the time to approval, thus providing financial incentives for sponsors to develop drugs for CF. These initiatives have induced industry sponsors into CF drug development.