Regulatory requirement
Encyclopedia
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
(EMA) 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.
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 culture
s and tissues, enzyme
s 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.
(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.
, distribution, metabolism
, and excretion patterns in humans (ADME
).
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.
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.
(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.
Drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
and drug development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
. 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) to establish these regulatory requirements. The European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) 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
Brussels
Brussels , officially the Brussels Region or Brussels-Capital Region , is the capital of Belgium and the de facto capital of the European Union...
in 1991, followed by ICH 2 in Orlando, Florida
Orlando, Florida
Orlando is a city in the central region of the U.S. state of Florida. It is the county seat of Orange County, and the center of the Greater Orlando metropolitan area. According to the 2010 US Census, the city had a population of 238,300, making Orlando the 79th largest city in the United States...
in 1993, and ICH 3 in Yokohama
Yokohama
is the capital city of Kanagawa Prefecture and the second largest city in Japan by population after Tokyo and most populous municipality of Japan. It lies on Tokyo Bay, south of Tokyo, in the Kantō region of the main island of Honshu...
, 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
Approved drug
In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo an extensive FDA approval process. This process involves first testing the drug on animals or in medical labs. If found to be safe by the FDA and approved for the next phase of study, the drug is then...
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 discoveryDrug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous 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
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, 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
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
") can run into the millions.
Biological Screening
Screening
One meaning of screening is the investigation of a great number of something looking for those with a particular problem or feature....
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 culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
s and tissues, enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s 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
Effective dose
Effective dose may refer to:*Effective dose the dose of pharmacologic agent which will have a therapeutic effect in some fraction of the population receiving the drug...
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
Active ingredient
An active ingredient is the substance of a pharmaceutical drug or a pharmaceutical ingredient and bulk active in medicine; in pesticide formulations active substance may be used. Some medications and pesticide products may contain more than one active ingredient...
, called excipients. Excipients are added to improve the taste of an oral product
Product (business)
In general, the product is defined as a "thing produced by labor or effort" or the "result of an act or a process", and stems from the verb produce, from the Latin prōdūce ' lead or bring forth'. Since 1575, the word "product" has referred to anything produced...
, 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
Toxicology
Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...
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
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
testing until after the therapeutic potential of the product is established.
Regulatory Review
An Investigational New DrugInvestigational New Drug
The United States Food and Drug Administration's Investigational New Drug program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines before a marketing application for the drug has been approved...
(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 absorptionAbsorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
, distribution, metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, and excretion patterns in humans (ADME
ADME
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
).
Phase 2 Clinical Evaluation
A controlled clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
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 3 studies 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
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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 ApplicationNew drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
(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.See also
- Regulation of therapeutic goodsRegulation of therapeutic goodsThe regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency...
- GxPGxPGxP is a general term for Good Practice quality guidelines and regulations. These guidelines are used in many fields, including the pharmaceutical and food industries....
- Nuremberg CodeNuremberg CodeThe Nuremberg Code is a set of research ethics principles for human experimentation set as a result of the Subsequent Nuremberg Trials at the end of the Second World War.-Background:...
- Declaration of GenevaDeclaration of GenevaThe Declaration of Geneva was adopted by the General Assembly of the World Medical Association at Geneva in 1948 and amended in 1968, 1984, 1994, 2005 and 2006. It is a declaration of physicians' dedication to the humanitarian goals of medicine, a declaration that was especially important in view...
- Declaration of HelsinkiDeclaration of HelsinkiThe Declaration of Helsinki is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association . It is widely regarded as the cornerstone document of human research ethics...
- EudraLexEudraLexEudraLex is the collection of rules and regulations governing medicinal products in the European Union.-Volumes:EudraLex consists of 10 volumes:*Concerning Medicinal Products for Human use:**Volume 1 - Pharmaceutical Legislation....
- World Medical AssociationWorld Medical AssociationThe World Medical Association is an international and independent confederation of free professional Medical Associations, therefore representing physicians worldwide...
- Belmont ReportBelmont ReportThe Belmont Report is a report created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Its full title is the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission...
- Uppsala Monitoring CentreUppsala Monitoring CentreThe Uppsala Monitoring Centre , located in Uppsala, Sweden, is the field name for the World Health Organization Collaborating Centre for International Drug Monitoring...
- Council for International Organizations of Medical SciencesCouncil for International Organizations of Medical SciencesThe Council for International Organizations of Medical Sciences is an international, nongovernmental, not-for-profit organization established jointly by WHO and UNESCO in 1949....
(CIOMS) - Clinical Data Interchange Standards ConsortiumClinical Data Interchange Standards ConsortiumClinical Data Interchange Standards Consortium is a non-profit organization, whose mission is "to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of health-care". Their main project, the...
External links
- FDA Code of Federal Regulations Title 21 - FDA CFR Title 21 - Food and Drugs
- IND Rewrite Regulations (FDA Title 21 CFR Parts 312, 314, 511, and 514)
- Eudralex - The Rules Governing Medicinal Products in the European Union
- Pharmaceuticals and Medical Devices Agency (PMDA)
- Declaration of Tokyo - ethical code
- FDA Requirements Assistance and Library - Papers regarding FDA Code of Federal Regulations Predicate Rules