Once a target has been chosen, that choice often dictates which type of product may be most useful (Fig. 4.18). Drugs, which are typically small, hydrophobic compounds, are often able to penetrate cellular membranes and thereby gain access to intracellular targets (enzymes, kinases, regulatory proteins, etc.). Similarly, because such compounds may well be stable to the digestive conditions of the stomach and intestine, they may also be suitable for oral administration. In contrast, the nature, character, and size of biologics make them best suited for addressing extracellular targets (surface structures, antigens, receptors, soluble ligands, etc.) after par-enteral administration.

From the therapeutic standpoint, there are several ways in which to effect the disease process:

Inhibit the function of an enzyme or protein (ligand, receptor, signaling)

• Small-molecule inhibitor to block function

• Antibody to neutralize or remove a specific protein or structure

• Antisense RNA to prevent protein expression

Replace missing or defective proteins

• Administration of replacement protein or peptide

• Specific message induction

This point regarding regulatory considerations is quite important and emphasizes the value of frequent communication with regulatory bodies, such as the FDA (Fig. 4.19). The focuses of all regulatory agencies around the world are safety, efficacy, and manufacturing (reproducibility). Drug and biologic products usually have been regulated differently because of differences in the nature of the products, especially in the early research and development stages, as well as organizational differences. CDER, the Center for Drug Evaluation and Research, and CBER, the Center for Biologics Evaluation and Research, are the FDA groups responsible for regulation and approval of drugs and biological products, respectively. Certain types of studies cannot be readily done for biologics, such as some ADME (absorption, distribution, metabolism, and excretion). However, the core information and studies, especially the later clinical stages, have been and are pretty much consistent between drugs and biologics. Periodic changes in management and structure of the agency can certainly alter the requirements for submitting regulatory documents and initiating clinical trials, such as drugs and biological drugs being all placed under the auspices of CDER. The only biologics remaining with CBER are vaccines, cellular products, blood products, and antitoxins.

An important component of early product development is the utilization of available information to design what the product must do (Fig. 4.20). These properties then lead to the development of a document (viz., a product profile or specification sheet), which defines the properties of a successful product. Such specification sheets need only be a one-page document. Commonly included items are the unmet clinical need, a description of the product, the target indication, in vitro and in vivo potency, formulation, cost of goods, toxicity, preferred route and frequency of administration, and competition. It is also common in such documents to define "optimal" and "minimal" specifications. In this way, all research groups on the r Federal regulations exist to ensure that new therapeutics meet 3 criteria:

O Safe, effective, and manufactured reproducibly r Historically, drugs have been regulated by CDER (Center for Drug Evaluation and Research), while biologics have been regulated by CBER (Center for Biologics Evaluation and Research):

O FDA was established in 1931

C CBER was established during 1980's to address issues specific to biologics

C In 2003, review of all therapeutic products was transferred to CDER

For biologics, current process often involves a combined review by both agencies, depending upon the product and use:

O CDER - Therapeutic monoclonal antibodies, cytokines, growth factors, enzymes, and other novel proteins o CBER - Cellular products, blood products, vaccines, antitoxins r Regulatory pathway to clinic for biologics has often been shorter than for drugs:

C Certain requirements (multiple species tox, ADME, safety pharmacology, etc.) have not been relevant for most biologics r Importantly - Regulatory process continues to evolve! Fig. 4.19. Drugs & Biologics - Regulatory Considerations r Drugs - Small molecule organic compounds obtained by screening large libraries of natural or synthetic compounds:

c Molecular weight typically < 500 Daltons c Produced by chemical or semi-synthetic synthesis c Effective against intracellular and extracellular targets o Examples include most antibiotics and existing pharmaceuticals r Biologics - Protein-based therapeutics obtained from humans, animals and plants:

o Molecular weight typically > 5,000 Daltons (5 kDa) c Purified from natural sources or, more commonly, produced by recombinant methods or monoclonal anitbodies c Primarily effective against extracellular targets c Generally administered by injection o Examples include antibodies, hormones, enzymes, cytokines and vaccines

Fig. 4.18. Product Choices - Drugs vs. Biologics r Once the target has been identified, the necessary properties of a potential therapeutic can be developed (what must the product do?):

o Inhibit target function (Lipitor, anti-TNF, anti-CD11a) c Stimulate target function (insulin, growth hormones) c Perform an enzymatic function (TPA)

o Kill specific cells (anti-Her2, antibiotics, most anti-cancer drugs)

r Important to develop a list of product specifications (when do I have a product candidate?):

c Provides a clear stopping point for screening c Must be realistic and based on current information o Minimizes endless discovery ( "better is the enemy of good")

r Most products fail as a result of unacceptable toxicity, inadequate therapeutic index, or low potency

Fig. 4.20. Product Design and Selection r Label claims describe FDA-approved use of the drug and are found in Package Insert:

O Disease indication - What the drug is intended to treat O Target population - Ages or groups who need the drug O Route of delivery - IV injection, oral, nasal, etc. o Observed benefit - The improvement seen in clinical trials o Safety issues - Any toxicities noted in animals and humans r Potential label claims influence many aspects of drug development:

C Discovery and non-clinical expectations and plans o Development of product specifications (what must it do?) C Identification of go/no-go decision points C Clinical testing plan P Marketing plan

Fig. 4.21. Consider Potential Product label Early

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