Drug development
Encyclopedia
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
. It includes pre-clinical research (microorganisms/animals) and clinical trials (on humans) and may include the step of obtaining regulatory approval to market the drug.
Pre-clinical.
New Chemical Entities
(NCEs)(also known as New Molecular Entities (NMEs)) are compounds which emerge from the process of drug discovery
. These will have promising activity against a particular biological target thought to be important in disease; however, little will be known about the safety, toxicity
, pharmacokinetics
and metabolism
of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("first-in-man
" (FIM) or First Human Dose (FHD)).
In addition, drug development is required to establish the physicochemical properties of the NCE: its chemical makeup, stability, solubility. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a synthetic chemist, it can be manufactured on the kilogram and then on the ton
scale. It will be further examined for its suitability to be made into capsules, tablets, aeresol, intramuscular injectable, subcuteneous injectable, or intravenous formulations
. Together these processes are known in preclinical development as Chemistry, Manufacturing and Control (CMC).
Many aspects of drug development are focused on satisfying the regulatory requirement
s of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug is to be delivered through the skin). While, increasingly, these tests can be made using in vitro
methods (e.g. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined.
The information gathered from this pre-clinical testing, as well as information on CMC, and is submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug
application or IND. If the IND is approved, development moves to the clinical phase.
Clinical phase.
Clinical trials involves three steps:
Phase I trials, usually in healthy patients, determine safety and dosing
Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients
Phase III trials a large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients
The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility, reproduction, immune system, etc.). The compound will also be tested for its capability to cause cancer (carcinogenicity testing).
If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application
or NDA. Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials.
) to market - from discovery through clinical trials to approval - is complex and controversial. One element of the complexity is that the much-publicized final numbers often do not include just the simple out-of-pocket expenses, but also include "capital costs", which are included to take into account the long time period (often at least ten years) during which the out-of-pocket costs are expended; additionally it is often not stated whether a given figure includes the capitalized cost or comprises only out-of-pocket expenses. Another element of complexity is that all estimates are based on confidential information owned by drug companies, released by them voluntarily. There is currently no way to validate these numbers. The numbers are controversial, as drug companies use them to justify the prices of their drugs and various advocates for lower drug prices have challenged them. The controversy is not only between "high" and "low" -- the numbers also vary greatly at the high end.
A study published by Steve Paul et al in 2010 in Nature Reviews: Drug Discovery compares many of the studies, provides both capitalized and out-of-pocket costs for each, and lays out the assumptions each makes: see Supplemental Box 2. The authors offer their own estimate of the capitalized cost as being ~$1.8B, with out-of-pocket costs of ~$870M.
Studies published by diMasi et al. in 2003, report an average pre-tax, capitalized cost of approximately $800 million to bring a new drug to market. A study published in 2006 estimates that costs vary from around $500 million to $2 billion depending on the therapy or the developing firm. A study published in 2010 in the journal Health Economics, including an author from the US Federal Trade Commission
, was critical of the methods used by diMasi et al. but came up with a higher estimate of ~$1.2B. Critic Marcia Angell
, M.D., a former editor of the New England Journal of Medicine
, has called that number grossly inflated, and estimates that the total is closer to $100 million. A 2011 study also critical of the diMasi methods, puts average costs at $55 million.
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...
. It includes pre-clinical research (microorganisms/animals) and clinical trials (on humans) and may include the step of obtaining regulatory approval to market the drug.
New Chemical Entity (NCE) development
Broadly the process can be divided into pre-clinical and clinical work.Pre-clinical.
New Chemical Entities
New chemical entity
A new chemical entity , or new molecular entity , is, according to the U.S. Food and Drug Administration, a drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act.An active moiety is a...
(NCEs)(also known as New Molecular Entities (NMEs)) are compounds which emerge from the process of drug discovery
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...
. These will have promising activity against a particular biological target thought to be important in disease; however, little will be known about the safety, 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...
, pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
and 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...
of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("first-in-man
First-in-man study
A first-in-man study is a clinical trial where a medical procedure, previously developed and assessed through in vitro or animal testing, or through mathematical modelling is tested on human subjects for the first time....
" (FIM) or First Human Dose (FHD)).
In addition, drug development is required to establish the physicochemical properties of the NCE: its chemical makeup, stability, solubility. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a synthetic chemist, it can be manufactured on the kilogram and then on the ton
Ton
The ton is a unit of measure. It has a long history and has acquired a number of meanings and uses over the years. It is used principally as a unit of weight, and as a unit of volume. It can also be used as a measure of energy, for truck classification, or as a colloquial term.It is derived from...
scale. It will be further examined for its suitability to be made into capsules, tablets, aeresol, intramuscular injectable, subcuteneous injectable, or intravenous formulations
Formulations
Formulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formula...
. Together these processes are known in preclinical development as Chemistry, Manufacturing and Control (CMC).
Many aspects of drug development are focused on satisfying the regulatory requirement
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 to establish these...
s of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug is to be delivered through the skin). While, increasingly, these tests can be made using in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
methods (e.g. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined.
The information gathered from this pre-clinical testing, as well as information on CMC, and is submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug
Investigational 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...
application or IND. If the IND is approved, development moves to the clinical phase.
Clinical phase.
Clinical trials involves three steps:
Phase I trials, usually in healthy patients, determine safety and dosing
Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients
Phase III trials a large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients
The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility, reproduction, immune system, etc.). The compound will also be tested for its capability to cause cancer (carcinogenicity testing).
If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application
New 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...
or NDA. Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials.
Cost
The full of cost of bringing a new drug (i.e. a drug that is a new chemical entityNew chemical entity
A new chemical entity , or new molecular entity , is, according to the U.S. Food and Drug Administration, a drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act.An active moiety is a...
) to market - from discovery through clinical trials to approval - is complex and controversial. One element of the complexity is that the much-publicized final numbers often do not include just the simple out-of-pocket expenses, but also include "capital costs", which are included to take into account the long time period (often at least ten years) during which the out-of-pocket costs are expended; additionally it is often not stated whether a given figure includes the capitalized cost or comprises only out-of-pocket expenses. Another element of complexity is that all estimates are based on confidential information owned by drug companies, released by them voluntarily. There is currently no way to validate these numbers. The numbers are controversial, as drug companies use them to justify the prices of their drugs and various advocates for lower drug prices have challenged them. The controversy is not only between "high" and "low" -- the numbers also vary greatly at the high end.
A study published by Steve Paul et al in 2010 in Nature Reviews: Drug Discovery compares many of the studies, provides both capitalized and out-of-pocket costs for each, and lays out the assumptions each makes: see Supplemental Box 2. The authors offer their own estimate of the capitalized cost as being ~$1.8B, with out-of-pocket costs of ~$870M.
Studies published by diMasi et al. in 2003, report an average pre-tax, capitalized cost of approximately $800 million to bring a new drug to market. A study published in 2006 estimates that costs vary from around $500 million to $2 billion depending on the therapy or the developing firm. A study published in 2010 in the journal Health Economics, including an author from the US Federal Trade Commission
Federal Trade Commission
The Federal Trade Commission is an independent agency of the United States government, established in 1914 by the Federal Trade Commission Act...
, was critical of the methods used by diMasi et al. but came up with a higher estimate of ~$1.2B. Critic Marcia Angell
Marcia Angell
Marcia Angell, M.D. is an American physician, author, and the first woman to serve as editor-in-chief of the New England Journal of Medicine...
, M.D., a former editor of the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
, has called that number grossly inflated, and estimates that the total is closer to $100 million. A 2011 study also critical of the diMasi methods, puts average costs at $55 million.
Success rate
Candidates for a new drug to treat a disease might theoretically include from 5,000 to 10,000 chemical compounds. On average about 250 of these will show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these will qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that start phase I trials are eventually approved for marketing.See also
- Clinical trialClinical trialClinical 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...
- 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....
- Drug designDrug designDrug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
- Drug discoveryDrug discoveryIn 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...
- Drug repositioningDrug repositioningDrug repositioning is the application of known drugs and compounds to new indications .- Drug repositioning :...
- Generic drugGeneric drugA generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, a consensus between the U.S. Food and Drug AdministrationFood and Drug AdministrationThe 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), EUEurope, the Middle East and AfricaEurope, the Middle East and Africa, usually abbreviated to EMEA, is a regional designation used for government, marketing and business purposes...
, and JapanMinistry of Health, Labour and Welfare (Japan)The ' is a cabinet level ministry of the Japanese government. It is commonly known as Kōrō-shō in Japan. This ministry provides regulations on maximum residue limits for agricultural chemicals in foods, basic food and drug regulations, standards for foods, food additives, etc.It was formed with...
. - Investigational New DrugInvestigational New DrugThe 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...
, FDA application/permission to start clinical trials - List of pharmaceutical companies
- Pre-clinical developmentPre-clinical developmentIn drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
External links
- Drug Development Technology Projects, companies and industry news
- CDER Drug and Biologic Approval Reports
- International Union of Basic and Clinical Pharmacology