Drug Discovery and Development Today

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Drug discovery today is a very complex, competitive, delicate and risky process. This is partly because the pharmaceutical industry is the epitome of the ‘winner-takes-all’ philosophy where the first company to patent a drug gets exclusive rights for its use for many years - a passage way to huge financial gains (Duggan et al, 2000). The runner-up gets absolutely nothing (Duggan et al, 2000). The drug discovery, development and approvals process, from conception to market is summarized in

Drug companies continuously analyze thousands of compounds, seeking ones of therapeutic value (Klein & Tabarrok, 2003). Drug testing begins at the preclinical stage (Klein & Tabarrok, 2003; Wierenga & Eaton, 2004). In this phase, the manufacturer completes laboratory and animal studies of the compound, to show biological activity against the targeted disease and to verify the safety of the compound (Klein & Tabarrok, 2003; Wierenga & Eaton, 2004). The preclinical testing phase lasts anywhere from three to seven years (Klein & Tabarrok, 2003; Wierenga & Eaton, 2004). Of five thousand compounds tested, approximately five will appear promising enough to induce the company to file an Investigational New Drug Application (IND) (Klein & Tabarrok, 2003; PhRMA, 2003; Wierenga & Eaton, 2004). The IND shows results of previous experiments, how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufactured (Wierenga & Eaton, 2004). If the FDA approves the IND, an Institutional Review Board (IRB) is also required to give its approval before the manufacturer can be permitted to begin the first phase of development (Klein & Tabarrok, 2003; Wierenga & Eaton, 2004). The FDA strictly monitors the membership of the IRB to ensure that it is composed of “at least five members including at least one scientific member, one nonscientific member, at least one person not affiliated with the research institution, no members with conflicts of interests, both genders if at all possible, and so forth” (Klein & Tabarrok, 2003). The IND stage consists of three phases:

Phase I

In phase I, the pharmaceutical companies conduct clinical trials using anywhere from twenty to a hundred healthy volunteers to determine the drug's basic properties and safety in humans (Pratap, 2004). This test stage can last for one to two years (PhRMA, 2003).

Phase II

In phase II, efficacy trials begin as the drug is administered to several hundred volunteer patients (Pratap, 2004). In this phase, the patients are given the drug to evaluate how effective it is against the observed signs and symptoms of the disease (Pratap, 2004). The possible side effects are also evaluated (Pratap, 2004). At the end of phase II, the manufacturer meets with the FDA to discuss the development process, continued human testing, any concerns the FDA may have, and the protocols for phase III, which is usually the most extensive and most expensive part of drug development (Klein & Tabarrok, 2003).

Phase III

Phase III testing involves one to several thousand patient volunteers and is by far the most detailed, time consuming and expensive clinical trial phase (Klein & Tabarrok, 2003; PhRMA, 2003; Wierenga & Eaton, 2004). In this phase, the drug is administered to patients to get more information on its effectiveness, safety, optimal dosage and rare side effects (Pratap, 2004; Wierenga & Eaton, 2004). This essentially is a risk-benefit analysis that allows the FDA to decide on the overall benefit of a drug, measured against the observed risks and side effects (Klein & Tabarrok, 2003).
Once Phase III is complete, the manufacturer analyzes all of the data and files a New Drug Application (NDA) with FDA if the data successfully demonstrate safety and effectiveness (Klein & Tabarrok, 2003; Wierenga & Eaton, 2004). Mahlich (2001) describes a Phase IV where the new drug, having been successfully registered is continuously monitored “to collect and evaluate information on rare side-effects, to quantify the therapeutic risks and to determine possible new areas of indication”.

During the IND phases (Phases I – III) there are a few accommodations that can be allowed the drug manufacturers. The manufacturer can receive an “accelerated development” status, to allow for the treatment of patients with “life-threatening or seriously debilitating conditions, for which no other drug treatment exists”, or a “treatment IND” status to allow for treatment of patients with “immediately life-threatening” conditions (Klein & Tabarrok, 2003). The NDA must contain all of the scientific information that the company has gathered and typically run 100,000 pages or more (Wierenga & Eaton, 2004). Review of the NDA typically lasts one to two years, bringing total drug development and approval (that is, the IND and NDA stages) to approximately nine years (Klein & Tabarrok, 2003). During the NDA stage, the FDA consults advisory committees made of experts to obtain a broader range of advice on drug safety, effectiveness, and labeling (Klein & Tabarrok, 2003). Once approved, the drug may be marketed with FDA regulated labeling (Klein & Tabarrok, 2003). The FDA also gathers safety information as the drug is used and adverse events are reported, and it will occasionally request changes in labeling or will submit press releases as new contraindications arise (Klein & Tabarrok, 2003). If adverse events appear to be systematic and serious, the FDA may withdraw a product from the market (Klein & Tabarrok, 2003).

For every 5,000 or so compounds tested, approximately five will appear promising enough to file an IND (Klein & Tabarrok, 2003; PhRMA, 2003; Wierenga & Eaton, 2004). Of those five, approximately one will be approved by the FDA and make it to market (Klein & Tabarrok, 2003; PhRMA, 2003; Wierenga & Eaton, 2004).

For a detailed discussion of the drug development process, please refer to the FDA handbook on this subject (http://www.fda.gov/cder/handbook/develop.htm).