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Fig. 4.9. Goals of Discovery Research for every 50 entering preclinical development), even starting with a recombinant human protein with known activity is no guarantee of clinical and market success. For example, at Amgen, GDNF (glial-derived neurotrophic factor) has been demonstrated in vitro cell cultures to arrest death of or heal the brain cells associated with Parkinson disease and even dramatically improved the signs of parkinsonism in primate animal models. However, GDNF was a failure in human trials without significant improvement in the clinical signs and symptoms of the disease. Alternatively, an unexpected adverse effect from such a protein, which may very closely resemble the natural protein, can occur to stop its development. For example, a thrombopoietic factor for platelet disorders was found and was quite active but for some unknown reason produced antibodies against the not only the protein but also against the naturally occurring thrombopoietin, which was a life-threatening complication.

Some of the issues that complicate the drug development process include the following eleven examples:

• disease biology is incompletely understood

• in vitro assays may not accurately mimic disease process

• in vivo models may not accurately mimic disease process

• acute onset disease animal models may not accurately mimic chronic diseases in humans

• actions of the compound are inherently different in humans than in animals

• human population is very heterogeneous (laboratory animals are not)

• some toxicity issues only show up in humans

• target and compound selection are not in sync with the complexity of disease physiology

• the pharmacokinetics and clearance of molecules may differ between humans and animal model

• proteins (recombinant, antibodies, or peptides) may lead to neutralizing antibodies reducing or preventing activity

• biologic molecules may be so large or complex in structure that formulations become impossible challenges to get the product to the site of action

These issues have helped revive the concept of systems biology in drug discovery, which seeks to understand physiology and disease processes at the levels of molecular pathways, regulatory networks, cells tissues, organs, and whole organisms [11]. With such an understanding, it is hoped that drug discovery targets and their therapeutic drug candidates can be more effectively and rigorously identified and prioritized.

Here then is a summary of eight goals that discovery research is trying to accomplish (Fig. 4.9). Several topics deserve further comment:

Conduct critical studies early: It is imperative that experiments be designed to evaluate the actual validity of the target and the value of the lead compound, and that these studies be conducted as early as possible. Quite frequently, such studies are often delayed for fear that the project might be killed, but it is far better to stop an unpromising project early than to spend more time and money simply postponing the decision. Besides, terminating one program often allows more time to pursue (or create) new, more promising ones. Biomarkers as noted above are important tools to achieve these goals.

Expansion of indications: Because drug development is so costly and time consuming, one approach that takes further advantage of development dollars already spent is to explore additional indications for approved therapeutics. Such studies can involve entirely new indications, or alterations to the therapeutic (formulation, delivery route, delivery devices, etc.) for existing indication (more later). Although new indications and uses often require additional time for development and testing, they avoid additional discovery costs and effectively build on existing data.

Intellectual property: Patents are critical components of any development program, as they are a form of "property" that can be sold or traded. In essence, patents are legal documents that entitle the owner to prevent others from making, using, or selling the invention for a limited period of time. If that invention is a new therapeutic, then the owner is the only one who has the right to manufacture and market that therapeutic. Similarly, if the invention covers a specific process (such as the production of recombinant proteins in mammalian cells), then other companies interested in selling their different recombinant proteins (produced by the same method, that is, invention) may need a license to that patent in order to market their products. Importantly, although all aspects of the development process can generate useful intellectual property (including development and clinical trials), it is often the discovery phase that has the earliest opportunities to identify and protect new areas. Whether it is new therapeutic targets, new experimental therapeutics, or new indications, much of the earliest data and results that are patentable are identified during discovery. Thus, much of a product's real value comes from the intellectual property that surrounds it, and much of this intellectual property begins with discovery research. Patents usually occur early in the life of a molecule that becomes a product, but new patents are constantly being pursued throughout the product's life cycle to improve the manufacturing efficiency, protect related molecules, or find new useful formulations.

In order to accomplish these goals, what does discovery need to do be successful (Fig. 4.10)? As before, some of these six areas deserve further comment:

New targets, compounds and disease pathology: where do they come from? Historically, drug development companies relied upon internal research organizations and groups for the identification of new targets and therapeutics. Recently, however, more and more development programs are the result of strategic partnerships between drug development companies and other companies or academic laboratories r Access to appropriate sources of new targets and compounds r Detailed knowledge of the basic biology for the targeted disease process r Ability to rapidly analyze targets and potential therapeutics r Understanding of the regulatory issues and requirements r Recognition that discovery and development decisions involve multiple groups (research, development, legal, marketing, management, etc.) r An understanding that terminating unsuccessful projects is critical, crucial and beneficial

Fig. 4.10. Needs of Discovery Research

(more later). Biotechnology companies are a major source for new disease knowledge, targets, and compounds; about 3,300 companies existed in United States and Europe in 2003.

Interacting with multiple groups. Decisions in any organization can be a complex process, and those involving drug discovery and development are no exception. For those involved in the discovery process, it is important to recognize that decisions are multifaceted and involve numerous groups. Thus, in addition to input from the research groups, also involved are legal (is there "freedom to operate" or license issues?), technical development (can it be purified and formulated?), manufacturing (can we make it?), regulatory (is there an approval path?), marketing (can we sell it?) and management (is it good for business?). Along with such varied groups playing key roles, the processes of teams, planning, and decision making require much more emphasis even at early stages such that the right people are engaged at the right time with the right information for the best possible decisions to be made by product teams and management. Portfolio and project planning management (PPM) have become key roles at the research stage as well.

Terminating unsuccessful projects. Terminating a project is often quite difficult, as they tend to gain a life of their own. From the scientist who thought of the idea to the marketing person who really likes the idea to upper management who really wants the idea to work, everyone hopes that each project will succeed. That said, it should be clear from the foregoing discussion that in fact most projects do not. And, for this reason, it is critical to terminate unsuccessful projects as early as possible, so effort and money can be spent on potentially more promising projects.

Despite the fact that the highest drug sales are for products that treat gastrointestinal (antiulcerants) and cardiovascular (cholesterol and triglyceride reducers) diseases, both biotech and pharma companies are focusing most of their development and clinical efforts on cancer, infectious diseases, and central nervous system disorders (Fig. 4.11) [12]. One rationale for this paradox is the medical need of patients, the advancing science, and the opportunity for sales. Neurologic disorders, especially neuromuscular and Alzheimer's, are quite prevalent without good treatments, representing high m

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