Another approach involves testing compounds made naturally by microscopic organisms. Candidates include fungi, viruses, and molds, such as those that led to penicillin and other antibiotics. Scientists grow the microorganisms in what is known as a fermentation broth, with one type of organism per broth. Sometimes, 100,000 or more broths are tested to see whether any compound made by a microorganism has a desirable effect.

Animal testing. In animal testing, drug companies make every effort to use as few animals as possible and to ensure their humane and proper care. Generally, two or more species (one rodent, one nonrodent) are tested because a drug may affect one species differently from another. Animal testing is used to measure how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its breakdown products (metabolites), and how quickly the drug and its metabolites are excreted from the body.

Clinical Studies

During this phase, the results of the preclinical tests are submitted to the monitoring agency (i.e., FDA) for review before the drug can be tested in humans. An investigational new drug (IND) application is filed and must be approved before any human testing begins. Approximately one in five new IND request makes it to the marketplace.

Phase 1: Safety studies. This phase begins trials in humans that test a compound for safety, tolerance, and pharmacokinetics. The Phase 1 trials usually employ normal (i.e., healthy) volunteers and may expose up to 50 individuals to the drug. For most therapeutic biologics and any known toxic compounds, such as anti-cancer agents, only patients with the targeted illness would be used.

Phase 2: Efficacy studies. These are the first studies (usually) to define efficacy. In general, 100 to 300 patients enter into various closely monitored clinical trials during this phase. Dose and dosing regimens are assessed for magnitude and duration of effect during this phase. Some companies further differentiate this phase into Phase 2A for studies designed to set dosing and Phase 2B for studies designed to determine efficacy.

Phase 3: Extensive clinical testing. These are expanded controlled and uncontrolled clinical trials intended to gather additional evidence of effectiveness for specific indications and to better understand safety and drug-related adverse effects. Phase 3 trials are usually large multicenter trials, which collect substantial safety experience and may include specialized studies needed for labeling (e.g., pediatric or elderly, comparative agents). Phase 3 trials normally include between 1,000 and 3,000 patients.

Phase 4: Postapproval studies. This phase is activated or requested only by the FDA when a drug is approved for marketing. There are many reasons for performing Phase 4 studies, including:

To elucidate the incidence of adverse reactions.

Large scale, long-term studies to determine the effect of a drug on morbidity or mortality.

To study a patient population not previously studied (e.g., children).

Marketing-oriented comparison studies against competitor products.

New Drug Application (NDA) Review

The new drug application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale in the United States. To obtain this kind of authorization, a drug manufacturer submits an NDA nonclinical (animal) and clinical (human) test data and analyses, drug information, and descriptions of manufacturing procedures.

The project manager should ensure that all the necessary NDA documentation is correct and in good order. An NDA must provide sufficient information, data, and analyses to permit FDA reviewers to reach several key decisions, including:

Whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh its risks.

Whether the drugs proposed labeling is appropriate, and, if not, what the drugs labeling should contain.

Whether the methods used in manufacturing the drug and the controls used to maintain the drugs quality are adequate to preserve the drugs identity, strength, quality, and purity.

The purpose of preclinical work animal pharmacology/ toxicology testing is to develop adequate data to obtain a decision that it is reasonably safe to proceed with human trials of the drug. Clinical trials represent the ultimate premarket testing ground for unapproved drugs. During these trials, an investigational compound is administered to humans and is evaluated for its safety and effectiveness in treating, preventing, or diagnosing a specific disease or condition. The results of this testing comprise the single most important factor in the approval or disapproval of a new

drug.

Although the goal of clinical trials is to obtain safety and effectiveness data, the overriding consideration in these studies is the safety of those in the trials. The Center for Drug Evaluation & Research (CDER) monitors the study design and conduct of clinical trials to ensure that people in the trials are not exposed to unnecessary risks.

Typical Drug Project Team

The following team members are required for drug-related projects, which aim to register and approve public accessible drugs:

Doctors.

Biologists. Biochemists. Microbiologists. Chemists.

Pharmacokinetics, formulation, and toxicology expertise and manpower. Computer modeler. Project manager. Project coordinator.

The methodology is a long and often complex series of challenges facing the project team. Project expertise and commitment are needed to make it work. Most importantly, success is built around how the team is led and managed. The project may fail at any stage of the new drug development because of poor efficacy, inability to formulate properly, toxicity, uncompetitive costs, or many other project-related factors.

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