This paper traces the complete drug development process from initial discovery to market approval. It begins with the historical evolution of U.S. federal drug regulation, starting with the 1906 Food and Drug Act, and proceeds through the preclinical stage of compound identification, formulation, and toxicity testing. The paper then details the Investigational New Drug (IND) application process and the three formal phases of clinical investigation required by the FDA, including sample sizes, durations, and passage rates. It also addresses the role of randomized controlled trials in Phase 3 evaluation, the New Drug Application (NDA) review process, and postmarketing (Phase 4) surveillance. Throughout, the paper emphasizes the regulatory, scientific, and commercial dimensions of bringing a new pharmaceutical to market.
The process of drug development is a complex one. The pharmaceutical industry is required to adhere to strict governmental regulations set out by the Food and Drug Administration (FDA), which involve numerous phases of testing and clinical trials, close monitoring of a drug's effects on users, its stability, dosage forms, and related concerns. This paper describes the drug development process as it proceeds from nature to the market.
Drugs that eventually reach the marketplace can come from a variety of sources — plants, animals, microbes, synthetic chemistry, biotechnology, and even modified molecules. Years of research and billions of dollars are invested by pharmaceutical companies as they seek out new potential drugs. All of this effort has resulted in the FDA's approval of 1,200 drugs for the marketplace since 1950 (Munos 960). The formulas that have gone into producing these drugs are diverse, with some changing over time in order to meet continually reassessed standards and updated regulations.
While drugs have been produced by societies around the world throughout history, the 20th century saw the beginning of a vast federal initiative to provide oversight of the drug industry for the first time in the United States. This began with the Food and Drug Act of 1906 — the first law passed at the federal level regarding the regulation of drug standards. Various acts throughout the 20th century amended the statutes contained in this early legislation, such as the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938, the Durham-Humphrey Amendment of 1952, and the Kefauver-Harris Amendments of 1962. Each of these was passed to address issues that arose in the marketplace regarding the safety of dispensation, the safety of the drugs themselves, and the authenticity of drug claims.
Today, new drugs must be sponsored in order to obtain FDA approval. Drug companies are typically the ones to sponsor new pharmaceuticals, and as sponsors they are responsible for providing evidence that the new product is safe, effective, and performs as indicated by the product description. Moreover, as a result of the development of industry regulations, drug companies must also follow protocols regarding the manufacturing, packaging, labeling, and shipping of drugs so that risks of counterfeiting and misidentification are reduced. Currently, radio-frequency identification (RFID) technology is being discussed in the industry as a means for drug manufacturers to work with regulators on maintaining high standards in shipping, tracking, and receiving (Coustasse, Kimble, Stanton, Naylor).
Before drugs arrive at the clinical stage, there is a long process of development that begins with the preclinical phase. This is essentially the phase in which a new drug is born — conceived from natural sources, synthetic sources, or genetic manipulation. Through the process of drug discovery, the ideal compound is identified or constructed, its biology characterized, and its pharmacological uses determined. Testing at this phase includes toxicity, carcinogenicity, mutagenicity, and more; animals are typically used as test subjects during this stage.
The preclinical phase continues with further evaluation of compounds identified as potentially effective. The focus at this point is on achieving a stable formulation of the compound through analysis of its chemical and physical properties. Issues regarding stability of form include a drug's solubility, its rate of dissolution, its partition coefficient, and so on. An initial product is then created for the first clinical trial. Companies are legally obliged to ensure that this product is formulated according to the FDA's Current Good Manufacturing Practice (CGMP) guidelines (Shukla, Vishnoi, Das).
Before testing using human subjects, the drug's sponsoring company must file an Investigational New Drug (IND) application with the FDA. The Institutional Review Board must give its approval before the application can be submitted. The FDA then takes 30 days to review the application before granting or denying approval. If approved, a Clinical Hold is issued, which allows the company to proceed with its clinical trial using human subjects.
There are three phases of clinical investigation that a product must pass through following the FDA's approval of the IND application. Phase 1 consists of the drug being tested on a small sample of healthy volunteers. The number of participants may range from 20 to 100 persons, and the study lasts for several months as the drug's toxicity and the sample's tolerance are monitored, measured, and assessed. Only 67% of drugs pass this first phase of testing, which is "primarily concerned with drug safety, not efficacy" (Pocock 3). One of the key objectives is to determine a safe dosage level for the drug, which is established by monitoring side effects as the subject's dosage is gradually increased over time (Pocock 3).
Phase 2 trials utilize a far larger sample, with up to several hundred human subjects participating, though the number commonly falls between 100 and 200 participants (Pocock 3). The purpose of Phase 2 trials is to measure the actual effectiveness of the drug on patients who have the condition the drug is intended to address. Safety continues to be monitored and optimal dosage levels are ascertained. Phase 2 trials last approximately two years, and fewer than 50% of drugs successfully pass beyond this period.
"How randomized controlled trials assess drug efficacy"
"NDA review process and postmarket consumer monitoring"
The process by which a drug is conceived from natural, synthetic, or manipulated sources, tested, and marketed to consumers is a lengthy one that takes years and involves many hundreds of participants, researchers, and regulators. Because the pharmaceutical industry is so large today and regulations are so pervasive, these procedures are necessary to safeguard both the public and the companies that manufacture drugs. By following the guidelines put forward by the FDA, companies can begin the process of drug development with complete awareness of what is in store.
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