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 or 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 medicinal
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, aerosol, intramuscular injectable,
subcutaneous 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 requirements
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 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 sick patients.
- Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients.
- (Phase 4): These are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies.
The process of drug development doesn't 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.
Cost
The full cost of bringing a new drug (i.e. a drug that is a new chemical entity) to market – from discovery
through clinical trials to approval – is complex and controversial; typically
it is hundreds of millions or billions of U.S. dollars. 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 one of
the drugs from the study to market. Also, this $800 million figure includes
opportunity costs of $400 million. 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
~$1.2 billion.
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. 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.
Novel initiatives to boost drug development
Novel initiatives include partnering between governmental
organizations and industry. The worlds largest such initiative is the
Innovative Medicines Initiative (IMI), and examples of major national
initiatives are Top Institute Pharma in the Netherlands
and Biopeople
in Denmark. In
2004, the FDA created the “Critical Path
Initiative” (CPI) project to guide the new drug development process.
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