Drug development

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Drug development is the process of bringing a new pharmaceutical drug to the market once
a lead compound has been identified through the process of drug discovery. It
includes preclinical research on microorganisms and animals, filing for regulatory status, such as
via the United States Food and Drug Administration for an investigational new drug to
initiate clinical trials on humans, and may include the step of obtaining regulatory approval with
a new drug application to market the drug.[1][2]

Contents

 1New chemical entity development

o 1.1Pre-clinical
o 1.2Clinical phase
 2Cost
 3Valuation
 4Success rate
 5Novel initiatives to boost development
 6See also
 7References
 8External links

New chemical entity development[edit]

Broadly, the process of drug development can be divided into preclinical and clinical work.
Timeline showing the various drug approval tracks and research phases [3]

Pre-clinical[edit]
Main article: Pre-clinical development
New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds
that emerge from the process of drug discovery. These have promising activity against a
particular biological target that is important in disease. However, little is 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 recommend the dose and schedule for the first use in a
human clinical trial ("first-in-human" [FIH] or First Human Dose [FHD], previously also known
as "first-in-man" [FIM]).
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 producing milligrams, to
manufacturing on the kilogram and ton scale. They further examine the product for suitability to
package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable,
or intravenous formulations. 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 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 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 through the skin). Increasingly, these
tests are made using in vitro methods (e.g., with isolated cells), but many tests can only be made
by using 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), as an Investigational New
Drug (IND) application. If the IND is approved, development moves to the clinical phase.
Clinical phase[edit]
Clinical trials involve three or four steps:[4]

 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 begins human
clinical trials. In addition to the tests required to move a novel 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). They must also test the compound for its potential to
cause cancer (carcinogenicity testing).
If a compound emerges from these tests with an acceptable toxicity and safety profile, and the
company 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 NCEs fail during drug development, either because they have unacceptable toxicity or
because they simply do not have the intended effect on the targeted disease as shown in clinical
trials.
A trend toward the collection of biomarker and genetic information from clinical trial
participants, and increasing investment by companies in this area, led by 2018 to fully half of all
drug trials collecting this information, the prevalence reaching above 80% among oncology
trials.[5]

Cost[edit]
Main article: Cost of drug development
One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug
to market as about US$1.8 billion and $870 million, respectively.[6] A median cost estimate of
2015-16 trials for development of 10 anti-cancer drugs was US$648 million.[7] In 2017, the
median cost of a pivotal trial across all clinical indications was $19 million.[8] The average cost
for a pivotal trial to demonstrate its equivalence or superiority to an existing approved drug was
$347 million.[8]
The full cost of bringing a new drug (i.e., new chemical entity) to market – from discovery
through clinical trials to approval – is complex and controversial. Typically, companies spend
tens to hundreds of millions of U.S. dollars.[8][9] One element of the complexity is that the much-
publicized final numbers often not only include the out-of-pocket expenses for conducting a
series of Phase I-III clinical trials, but also the capital costs of the long period (10 or more years)
during which the company must cover out-of-pocket costs for preclinical drug discovery.
In an analysis of the drug development costs for 98 companies over a decade, the average cost
per drug developed and approved by a single-drug company was $350 million.[10] But for
companies that approved between eight and 13 drugs over 10 years, the cost per drug went as
high as $5.5 billion, due mainly to geographic expansion for marketing and ongoing costs for
Phase IV trials and continuous monitoring for safety.[10]
Alternatives to conventional drug development have the objective for universities, governments,
and the pharmaceutical industry to collaborate and optimize resources.[11]

Valuation[edit]
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
trees, real options, or comparables.
The most important value drivers are the cost of capital or discount rate that is
used, phase 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 flows estimation.[12]
[13]

Success rate[edit]
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.[14] 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 started
Phase I trials were eventually approved for marketing.[15] In the time period of 2006 to 2015, the
success rate was 9.6%.[16] 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.[17] 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.[18]

Novel initiatives to boost development[edit]

Novel initiatives include partnering between governmental organizations and industry, such as
the European Innovative Medicines Initiative.[19] The US Food and Drug Administration created
the "Critical Path Initiative" to enhance innovation of drug development,[20] and
the Breakthrough Therapy 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.[21]

See also[edit]
 Council for International Organizations of Medical Sciences
 Drug design
 Drug repositioning
 Pharmaceutical engineering
 Pharmaceutical manufacturing
 Generic drug
 International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, a consensus between the U.S. Food and Drug
Administration (FDA), EU, and Japan.
 List of pharmaceutical companies

References[edit]
1. ^ Strovel, Jeffrey; Sittampalam, Sitta; Coussens, Nathan P.; Hughes, Michael; Inglese, James; Kurtz,
Andrew; Andalibi, Ali; Patton, Lavonne; Austin, Chris; Baltezor, Michael; Beckloff, Michael; Weingarten,
Michael; Weir, Scott (July 1, 2016). "Early Drug Discovery and Development Guidelines: For Academic
Researchers, Collaborators, and Start-up Companies". Assay Guidance Manual. Eli Lilly & Company and the
National Center for Advancing Translational Sciences.
2. ^ Taylor, David (2015). "The Pharmaceutical Industry and the Future of Drug Development". Issues
in Environmental Science and Technology. Royal Society of Chemistry: 1–33. doi:10.1039/9781782622345-
00001. ISBN 978-1-78262-189-8.
3. ^ Kessler, David A.; Feiden, Karyn L. (1995). "Faster Evaluation of Vital Drugs". Scientific
American. 272 (3): 48–54. Bibcode:1995SciAm.272c..48K. doi:10.1038/scientificamerican0395-
48. PMID 7871409.
4. ^ Ciociola AA; et al. (May 2014). "How drugs are developed and approved by the FDA: current
process and future directions". Am J Gastroenterol. 109 (5): 620–
3. doi:10.1038/ajg.2013.407. PMID 24796999.
5. ^ Miseta, Ed (August 17, 2018). "Gene Therapies Create Moral Dilemma For Clinical
Researchers". Clinical Leader. Pennsylvania, United States: VertMarkets, Inc.
6. ^ Paul, Steven M.; Mytelka, Daniel S.; Dunwiddie, Christopher T.; Persinger, Charles C.; Munos,
Bernard H.; Lindborg, Stacy R.; Schacht, Aaron L. (2010). "How to improve R&D productivity: The
pharmaceutical industry's grand challenge". Nature Reviews Drug Discovery. 9 (3): 203–
14. doi:10.1038/nrd3078. PMID 20168317.
7. ^ Prasad, Vinay; Mailankody, Sham (1 October 2017). "Research and development spending to bring
a single cancer drug to market and revenues after approval". JAMA Internal Medicine. 177 (11):
1569. doi:10.1001/jamainternmed.2017.3601. ISSN 2168-6106. PMC 5710275. PMID 28892524.
8. ^ Jump up to:a b c Moore, Thomas J.; Zhang, Hanzhe; Anderson, Gerard; Alexander, G. Caleb (1 October
2018). "Estimated costs of pivotal trials for novel therapeutic agents approved by the US Food and Drug
Administration, 2015-2016". JAMA Internal Medicine. 178 (11):
1451. doi:10.1001/jamainternmed.2018.3931. ISSN 2168-6106. PMC 6248200. PMID 30264133.
9. ^ Sertkaya, A; Wong, H. H.; Jessup, A; Beleche, T (2016). "Key cost drivers of pharmaceutical clinical
trials in the United States". Clinical Trials. 13 (2): 117–
26. doi:10.1177/1740774515625964. PMID 26908540.
10. ^ Jump up to:a b Herper, Matthew (11 August 2013). "The Cost Of Creating A New Drug Now $5 Billion,
Pushing Big Pharma To Change". Forbes, Pharma & Healthcare. Retrieved 17 July 2016.
11. ^ Maxmen A (2016). "Busting the billion-dollar myth: how to slash the cost of drug
development". Nature. 536 (7617): 388–
90. Bibcode:2016Natur.536..388M. doi:10.1038/536388a. PMID 27558048.
12. ^ Boris Bogdan and Ralph Villiger, "Valuation in Life Sciences. A Practical Guide", 2008, 2nd edition,
Springer Verlag.
13. ^ Nielsen, Nicolaj Hoejer "Financial valuation methods for biotechnology", 2010. "Archived
copy"  (PDF). Archived from the original  (PDF) on 2012-03-05. Retrieved 2014-11-25.
14. ^ Stratmann, Dr. H.G. (September 2010). "Bad Medicine: When Medical Research Goes
Wrong". Analog Science Fiction and Fact. CXXX (9): 20.
15. ^ "R&D costs are on the rise". Medical Marketing and Media. 38 (6): 14. June 1, 2003. Archived
from the original on October 18, 2016.
16. ^ "Clinical Development Success Rates 2006-2015"  (PDF). BIO Industry Analysis. June 2016.
17. ^ Wang Y. (2012). "Extracting Knowledge from Failed Development Programmes". Pharm
Med. 26 (2): 91–96. doi:10.1007/BF03256897.
18. ^ Herschel, M. (2012). "Portfolio Decisions in Early Development: Don't Throw Out the Baby with the
Bathwater". Pharm Med. 26 (2): 77–84. doi:10.1007/BF03256895. Archived from the original on 2012-06-16.
Retrieved 2012-06-12.
 19. ^ "About the Innovative Medicines Initiative". European Innovative Medicines Initiative. 2020.
Retrieved 24 January 2020.
20. ^ "Critical Path Initiative". US Food and Drug Administration. 23 April 2018. Retrieved 24
January 2020.
21. ^ "Breakthrough Therapy". US Food and Drug Administration. 4 January 2018. Retrieved 24
January 2020.

External links[edit]
 International Union of Basic and Clinical Pharmacology
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