Drug development is the process of bringing a new
pharmaceutical drug
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
to the market once a
lead compound
A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, b ...
has been identified through the process of
drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
. It includes
preclinical research
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
on microorganisms and animals, filing for regulatory status, such as via the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
for an
investigational new drug to initiate
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s on humans, and may include the step of obtaining
regulatory approval
Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. For ...
with a
new drug application to market the drug.
The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials – to approved vaccine or drug typically takes more than a decade.
New chemical entity development
Broadly, the process of drug development can be divided into preclinical and clinical work.
Pre-clinical
New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of
drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety,
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
,
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
, and
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
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 recommend the dose and schedule for the first use in a human clinical trial ("
first-in-human"
IHor First Human Dose
HD previously also known as "first-in-man"
IM.
In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a
medicinal chemist
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developmen ...
producing milligrams, to manufacturing on the kilogram and
ton
Ton is the name of any one of several units of measure. It has a long history and has acquired several meanings and uses.
Mainly it describes units of weight. Confusion can arise because ''ton'' can mean
* the long ton, which is 2,240 pounds
...
scale. They further examine the product for suitability to package as
capsules,
tablets, aerosol, intramuscular injectable, subcutaneous injectable, or
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
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 formul ...
. Together, these processes are known in preclinical and clinical development as ''chemistry, manufacturing, and control'' (CMC).
Many aspects of drug development focus on satisfying the regulatory requirements for a
new drug application. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. 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 on or through the skin). Such preliminary tests are made using ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.
The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
), as an
Investigational New Drug (IND) application. If the IND is approved, development moves to the clinical phase.
Clinical phase
Clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s involve three or four steps:
* Phase I trials, usually in healthy volunteers, determine safety and dosing.
* Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE.
* Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the
new drug application (NDA) stage.
* Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies.
The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).
If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it.
In the United States, this process is called a "
new drug application" or NDA.
Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials.
Critical reviews of drug development programs indicate that Phase II–III clinical trials fail due mainly to unknown toxic
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s (50% failure of Phase II
cardiology
Cardiology () is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart d ...
trials), and because of inadequate financing, trial design weaknesses, or poor trial execution.
A study covering clinical research in the 1980–90s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–15, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines.
The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures.
Cost
One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market was about US$1.8 billion and $870 million, respectively. A
median
In statistics and probability theory, the median is the value separating the higher half from the lower half of a data sample, a population, or a probability distribution. For a data set, it may be thought of as "the middle" value. The basic fe ...
cost estimate of 2015–16 trials for development of 10 anti-cancer drugs was $648 million.
In 2017, the median cost of a pivotal trial across all clinical indications was $19 million.
The average cost (2013 dollars) of
each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II
randomized controlled efficacy study, and $255 million for a
pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug,
possibly as high as $345 million.
The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $22 million.
The full cost of bringing a new drug (i.e.,
new chemical entity A new chemical entity (NCE) is, according to the U.S. Food and Drug Administration, a novel, small, chemical molecule drug that is undergoing clinical trials or has received a first approval (not a new use) by the FDA in any other application submit ...
) to market – from discovery through clinical trials to approval – is complex and controversial.
In a 2016 review of 106 drug candidates assessed through clinical trials, the total
capital expenditure
Capital expenditure or capital expense (capex or CAPEX) is the money an organization or corporate entity spends to buy, maintain, or improve its fixed assets, such as buildings, vehicles, equipment, or land. It is considered a capital expenditure ...
for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%.
Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for
Phase IV trials for continuous safety surveillance.
Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources. An example of a collaborative drug development initiative is
COVID Moonshot, an international
open-science project started in March 2020 with the goal of developing an un-
patented
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...
oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or oral ...
antiviral drug
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...
to treat
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
.
Valuation
The nature of a drug development project is characterised by high
attrition rates, large capital expenditures, and long timelines. This makes the valuation of such projects and companies a challenging task. Not all valuation methods can cope with these particularities. The most commonly used valuation methods are
risk-adjusted net present value (rNPV),
decision tree
A decision tree is a decision support tool that uses a tree-like model of decisions and their possible consequences, including chance event outcomes, resource costs, and utility. It is one way to display an algorithm that only contains condit ...
s,
real options
Real options valuation, also often termed real options analysis,Adam Borison (Stanford University)''Real Options Analysis: Where are the Emperor's Clothes?''
(ROV or ROA) applies option valuation techniques to capital budgeting decisions.Campbe ...
, or
comparables Comparables (or comps) is a real estate appraisal term referring to properties with characteristics that are similar to a subject property whose value is being sought. This can be accomplished either by a real estate agent who attempts to establish ...
.
The most important value drivers are the cost of capital or discount rate that is used,
phase
Phase or phases may refer to:
Science
*State of matter, or phase, one of the distinct forms in which matter can exist
*Phase (matter), a region of space throughout which all physical properties are essentially uniform
* Phase space, a mathematic ...
attributes such as duration, success rates, and costs, and the forecasted sales, including cost of goods and marketing and sales expenses. Less objective aspects like quality of the management or novelty of the technology should be reflected in the
cash flow
A cash flow is a real or virtual movement of money:
*a cash flow in its narrow sense is a payment (in a currency), especially from one central bank account to another; the term 'cash flow' is mostly used to describe payments that are expected ...
s estimation.
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 show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on humans. A study conducted by the
Tufts Center for the Study of Drug Development
The Tufts Center for the Study of Drug Development is an independent, academic, non-profit research center at Tufts University in Boston, dedicated to researching drug development. It was established in 1976 by American physician Louis Lasagna. Th ...
covering the 1980s and 1990s found that only 21.5 percent of drugs that started Phase I trials were eventually approved for marketing. In the time period of 2006 to 2015, the success rate was 9.6%. The high failure rates associated with pharmaceutical development are referred to as the "attrition rate" problem. Careful decision making during drug development is essential to avoid costly failures.
In many cases, intelligent programme and clinical trial design can prevent false negative results. Well-designed, dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data.
Computing initiatives
Novel initiatives include partnering between governmental organizations and industry, such as the European ''
Innovative Medicines Initiative
The Innovative Medicines Initiative (IMI) is a European initiative to improve the competitive situation of the European Union in the field of pharmaceutical research. The IMI is a joint initiative ( public-private partnership) of the DG Researc ...
''.
The US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
created the ''"Critical Path Initiative"'' to enhance innovation of drug development, and the ''
Breakthrough Therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
'' designation to expedite development and regulatory review of candidate drugs for which preliminary clinical evidence shows the drug candidate may substantially improve therapy for a serious disorder.
In March 2020, the
United States Department of Energy
The United States Department of Energy (DOE) is an executive department of the U.S. federal government that oversees U.S. national energy policy and manages the research and development of nuclear power and nuclear weapons in the United Stat ...
,
National Science Foundation
The National Science Foundation (NSF) is an independent agency of the United States government that supports fundamental research and education in all the non-medical fields of science and engineering. Its medical counterpart is the National I ...
,
NASA
The National Aeronautics and Space Administration (NASA ) is an independent agency of the US federal government responsible for the civil space program, aeronautics research, and space research.
NASA was established in 1958, succeeding t ...
, industry, and nine universities pooled resources to access supercomputers from
IBM, combined with cloud computing resources from
Hewlett Packard Enterprise
The Hewlett Packard Enterprise Company (HPE) is an American multinational information technology company based in Spring, Texas, United States.
HPE was founded on November 1, 2015, in Palo Alto, California, as part of the splitting of the H ...
,
Amazon
Amazon most often refers to:
* Amazons, a tribe of female warriors in Greek mythology
* Amazon rainforest, a rainforest covering most of the Amazon basin
* Amazon River, in South America
* Amazon (company), an American multinational technology c ...
,
Microsoft
Microsoft Corporation is an American multinational technology corporation producing computer software, consumer electronics, personal computers, and related services headquartered at the Microsoft Redmond campus located in Redmond, Washing ...
, and
Google
Google LLC () is an American multinational technology company focusing on search engine technology, online advertising, cloud computing, computer software, quantum computing, e-commerce, artificial intelligence, and consumer electronics. ...
, for drug discovery.
The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy.
In May 2020, the OpenPandemics – COVID-19 partnership between
Scripps Research
Scripps Research, previously known as The Scripps Research Institute (TSRI), is a nonprofit American medical research facility that focuses on research and education in the biomedical sciences. Headquartered in San Diego, California, the institu ...
and IBM's
World Community Grid
World Community Grid (WCG) is an effort to create the world's largest volunteer computing platform to tackle scientific research that benefits humanity. Launched on November 16, 2004, with proprietary Grid MP client from United Devices and addin ...
was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background
f connected home PCswhich will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19".
See also
*
Council for International Organizations of Medical Sciences
The Council for International Organizations of Medical Sciences (CIOMS) is an international non-governmental organization of 40 international, national, and associate member groups representing the biomedical science community. It was jointly est ...
*
Drug design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that acti ...
*
Drug repositioning
Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes.
Repurposing achievements
A number of successes have been achieved, the foremost including sildenafil (Viagra) for ere ...
*
Pharmaceutical engineering
Pharmaceutical engineering is a branch of engineering focused on discovering, formulating, and manufacturing medication, analytical and quality control processes, and on designing, building, and improving manufacturing sites that produce drugs. I ...
*
Pharmaceutical manufacturing
Pharmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as part of the pharmaceutical industry. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, gra ...
*
Generic drug
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
*
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, a consensus between the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA),
EU, and
Japan
Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
.
*
List of pharmaceutical companies
This listing is limited to those independent companies and subsidiaries notable enough to have their own articles in Wikipedia. Both going concerns and defunct firms are included, as well as firms that were part of the pharmaceutical industry ...
References
External links
International Union of Basic and Clinical Pharmacology
{{Pharmacy
Pharmaceutical industry
Drug discovery
Life sciences industry