Regulatory requirement

Regulatory requirements are part of the process of drug discovery and drug development. Regulatory requirements describe what is necessary for a new drug to be approved for marketing in any particular country. In the US, it is the function of the Food and Drug Administration (FDA) to establish these regulatory requirements. The European Medicines Agency (EMEA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) are also important regulatory authorities in drug development. These three agencies oversee the three largest markets for drug sales.

Historically, the various regulatory authorities have had their own methods for obtaining regulatory approval, however the rising cost of meeting the demands of differing regulations led to the establishment of an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in an attempt to co-ordinate and synthesize international regulatory requirements. The first Conference was held in Brussels in 1991, followed by ICH 2 in Orlando, Florida in 1993, and ICH 3 in Yokohama, Japan in 1995. The Fourth International Conference on Harmonisation, in July 1997, was once again in Brussels.

These systems of new drug approvals are extremely rigorous and costly. On average, it will cost a pharmaceutical company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 report by the Congressional Office of Technology Assessment. It takes 12 years on average for an experimental drug to travel from the laboratory to the medicine chest. Only five in 5,000 compounds that enter preclinical testing will actually progress into human clinical trials, and of these five, only one is likely to be approved by the regulatory authorities.

Drug Discovery and Development
The process of drug discovery and development begins with improvements in the understanding of disease. Basic scientific research will identify new biological targets which may be amenable to chemical alteration (e.g., to inhibit or stimulate an important enzyme, to alter a metabolic pathway, or to change cellular structure). New chemical entities (NCEs) can be produced through novel chemical synthesis or extracted from natural sources (plant, mineral, or animal). The number of compounds that can be produced based on the same general chemical structure (or "pharmacophore") can run into the millions.

Biological Screening and Pharmacological Testing: these are studies to explore the pharmacological activity and therapeutic potential of compounds. These tests involve the use of animals, isolated cell cultures and tissues, enzymes and cloned receptor sites as well as computer models. If the results of the tests suggest potential beneficial activity, then related compounds, each a unique structural modification of the original compound are tested to see which version of the molecule produces the highest level of pharmacological activity and demonstrates the most therapeutic promise, with the smallest number of potentially harmful biological properties.

Pharmaceutical Dosage Formulation and Stability Testing: The process of turning an active compound into a form and strength suitable for human use. A pharmaceutical product can take any one of a number of dosage forms (e.g., liquid, tablets, capsules, ointments, sprays, patches) and dosage strengths (e.g., 50. 100, 250, 500 milligrams.) The final formulation will include substances other than the active ingredient, called excipients. Excipients are added to improve the taste of an oral product, to allow the active ingredient to be compounded into stable tablets, to delay the drug's absorption into the body, or to prevent bacterial growth in liquid or cream preparations. The impact of each on the human body must be tested.

Toxicology and Safety Testing: Tests to determine the potential risk a compound poses to man and the environment. These studies involve the use of animals, tissue cultures, and other test systems to examine the relationship between factors such as dose level, frequency of administration, and duration of exposure to both the short- and long-term survival of living organisms. Tests provide information on the dose-response pattern of the compound and its toxic effects. Most toxicology and safety testing is conducted on new molecular entities prior to their human introduction, but companies can choose to delay long-term toxicity testing until after the therapeutic potential of the product is established.

Regulatory Review:
An Investigational New Drug (IND) Application is filed with the Food and Drug Administration prior to human testing. The IND application is a compilation of all known information about the compound, including how it is manufactured. It also includes a description of the clinical research plan for the product and the specific protocol for phase 1 human clinical trials. Unless the FDA specifically objects, the IND is automatically allowed after 30 days and clinical trials can begin.

Phase 1 Clinical Evaluation
The first testing of a new compound in human subjects, for the purpose of establishing the tolerance of healthy human subjects at different doses, defining its pharmacological effects at anticipated therapeutic levels, and studying its absorption, distribution, metabolism, and excretion patterns in humans (ADME).

Phase 2 Clinical Evaluation
A controlled clinical trial of a compound's potential usefulness and short term risks is conducted. A relatively small number of patients, usually no more than a few hundred, are enrolled in phase 2 studies. While a Phase 1 trial has the objective of determining safety and tolerability of a new drug, Phase 2 trials determine whether the drug actually works, and the effective dose.

Phase 3 Clinical Evaluation
In this phase a controlled and uncontrolled clinical trial of a drug's safety and effectiveness in hospital and outpatient settings is done. Phase 3 studies gather precise information on the drug's effectiveness for specific indications, determine whether the drug produces a broader range of adverse effects than those exhibited in the small study populations of phase 1 and 2 studies, and identify the best way of administering and using the drug for the purpose intended. If the drug is approved, this information forms the basis for deciding the content of the product label. Phase 3dies can involve several hundred to several thousand patients.

Development for manufacturing, quality control, engineering, and manufacturing design activities take place to establish a company's capacity to produce a product in large volume. Procedures are developed to ensure chemical stability, batch-to-batch uniformity, and overall product quality.

Bioavailability studies are conducted on healthy volunteers to document the rate of absorption and excretion from the body of a compound's active ingredients. Companies conduct bioavailability studies both at the beginning of human testing and just prior to marketing to show that the formulation used to demonstrate safety and efficacy in clinical trials is equivalent to the product that will be distributed for sale. Companies also conduct bioavailability studies on marketed products whenever they change the method used to administer the drug (e.g., from injection or oral dose form), the composition of the drug, the concentration of the active ingredient, or the manufacturing process used to produce the drug.

Regulatory Review: New Drug Application (NDA)
An application to the FDA for approval to market a new drug. All information about the drug gathered during the drug discovery and development process is assembled in the New Drug Application (NDA). During the review period, the FDA may ask the company for additional information about the product or seek clarification of the data contained in the application.

Post approval
Research experimental studies and surveillance activities undertaken after a drug is approved for marketing. Clinical trials conducted after a drug is marketed (referred to as phase 4 studies in the United States) are an important source of information on as yet undetected adverse outcomes, especially in populations that may not have been involved the premarketing trials (e.g., children, the elderly, pregnant women) and the drug's long-term morbidity and mortality profile. Regulatory authorities can require companies to conduct Phase 4 studies as a condition of market approval. Companies often conduct post-marketing studies in the absence of a regulatory mandate.