Reviews over the past decade have emphasized the large number of chemical compounds that must be examined as potential drugs during the development of each successfully approved agent. It has been estimated, that up to 10,000 compounds are examined for each therapeutic agent approved. The drug development process is also time consuming with drug development taking up to 16 years from the identification of a likely target to the approval of a drug effective against the target [16].

The development of every new drug begins with an idea. Often this idea or insight comes from a clinical observation, such as the recognition of a drug’s “side effect” during drug development for another indication, such as the observation of hair growth in subjects receiving a drug for hypertension. The idea or insight also often comes from advances in our understanding of disease pathophysiology. For example, the basic research that established the critical role of cytokines in inflammation, and the clinical research that confirmed that cytokines were elevated in inflammatory bowel disease (IBD), led to selection of tumor necrosis factor alpha as a target and to the development of anti-TNF agents for treatment of IBD. More recently the recognition of the role of IL-12 and IL-23 and IL-17 in inflammation has led to ongoing exploration of multiple targets in inflammatory diseases. The idea or insight leads to selection of a target, and the development of an agent effective against the target.

Drug development is generally divided into four stages: drug discovery, preclinical studies, clinical studies and regulatory review. As outlined in Fig. 43.1 it is estimated that nearly half of the time invested in drug development is spent in the drug discovery and preclinical stages (6.5 years), with the remainder spent in clinical trials (7 years) and in review by the regulatory agencies (1.5 years).

During the first stage, drug discovery, compounds are evaluated for their effectiveness against identified targets using in vitro assay systems and, when available, animal models. Once a promising candidate has been identified, that candidate is further examined in the preclinical stage with toxicology studies to evaluate the potential of the drug for mutagenicity/genotoxicity, teratogenicity and carcinogenicity. Pharmacological studies in animals are also undertaken in the preclinical stage to establish the pharmacokinetic (PK) parameters that define the absorption, distribution, metabolism, and excretion of the agent.

This preclinical toxicology data is combined with a clinical development plan to form an independent new drug (IND) application in the United States, or a clinical trial application (CTA) in European countries,

The IND is submitted to the FDA and/or CTA are submitted to the local health authority (the FDA in the US) at the end of preclinical studies and prior to the first in human phase 1 trial. The IND and CTA applications provide the reviewer at the health authority with the data required to ensure the potential safety of the candidate compound and provides the basis for clinical studies. The health authority (FDA, in the US) must approve the CTA (or IND) prior to trials in man.

The clinical study stage is divided into four phases.

The new drug application (NDA) submitted to the FDA and the CTA submitted to countries outside the US describe all data collected on a product and includes the chemistry, manufacturing process and quality control, animal toxicology, pharmacokinetics in animals and in man, and the clinical trial evidence on efficacy and safety. The results of phase 1–3 studies form the basis of a drug application (NDA). Only after review and approval of the NDA by the regulatory authority and receipt of a signed approval action letter can a drug be marketed.

Though there are many important clinical design features that must be considered during development of a clinical protocol we will review the four key design features of patient population, study design, the choice of endpoint and the dosing regimen.

The patient population to be studied in each trial must be carefully chosen to adequately define the study population. Competing priorities in this process include the need to minimize variability by tightly defining the population under study, while studying a population, which will allow physicians to generalize the results of the trial to the patients in their practice.

The study design chosen must match the hypothesis and the objective of the study. As an example, a classic design when the objective is to establish that an agent is effective in inducing response and remission would compare an active agent to a placebo in a population with active disease. In contrast when the objective is to establish that the agent maintains remission, a study, which randomizes subjects in remission to placebo or active agent and then follows the subjects long enough to ensure exacerbation of disease to occur in the subjects would be a good choice.

The choice of endpoint and the timing of the endpoint measure are key aspects of the trial. The endpoint should be validated and if possible have a history as being accepted by both regulatory authorities and opinion leaders. The choice of the timing of the assessment of the endpoint measure is also critical. In a trial designed to examine response to a drug, if the endpoint is established too early, the drug will not have time to induce response, if too late, placebo response may mask a true effect of the active agent.

The dose and dosing regimen must be chosen to ensure adequate serum levels of the active agent. This is generally based on preclinical PK and is confirmed by phase 1 PK.

Since 1938, when the Food, Drug and Cosmetic Act was passed, all new drugs brought to market in the US have required the approval of the FDA through the NDA process [17]. Though initially this review was restricted to ensuring the safety of new drugs, the NDA process was modified in 1962 with the Kefauver-Harris Amendments to the 1938 Act to add efficacy for intended use and confirmation that the benefits of the drug outweigh its know risks to the review of the NDA [12,15,17]. The FDA Modernization Act reduced review times, allowed for electronic submissions and proposed the first “pediatric rule” which mandated assessments of new drugs and biologic products for pediatric patients.

Though this first “pediatric rule” was overturned in a federal district court, in Dec. 2003, the Pediatric Research Equity Act (PREA) required pediatric studies for all NDAs and biologics license applications (BLAs) and here by re-established the pediatric rule. In 2002, the Best Pharmaceuticals for Children Act established a voluntary program that awards a 6-month exclusivity incentive to sponsors of marketed products that conducted pediatric studies in response to a written request from the FDA. The BPCA was the result of a partnership between the FDA and the NIH to promote pediatric studies for off-patent products.

In the EU, the Pediatric Regulation in Europe in effect since January, 2007 established a framework of rewards, incentives and obligations for pharmaceutical companies. The goal of this regulation was to encourage the development of medications for children which had been appropriately tested, authorized and formulated for use in children. The pediatric regulation established both a pediatric committee (PDCO) at the EMA, and a requirement for a pediatric investigation plan (PIP). The PIP is a binding roadmap that details the timing and measures proposed to demonstrate quality, safety and efficacy in the pediatric population. It specifies which population subsets need to be studied, by what means and by what date. The regulation specifies that the PIP should be submitted no later than upon completion of human PK studies in adults, potentially prior to Phase 2 Proof of concept trials. An approved PIP is required prior to a marketing authorization application filing for adult indications.