Drug development

"Drug research" redirects here. For the journal, see Drug Research (journal).

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.

New Chemical Entity (NCE) development

Regulation of therapeutic goods in the United States
Prescription drugs Over-the-counter drugs
Law Federal Food, Drug, and Cosmetic Act Comprehensive Drug Abuse Prevention and Control Act of 1970 Controlled Substances Act Prescription Drug Marketing Act Drug Price Competition and Patent Term Restoration Act Hatch-Waxman exemption
Government agencies Department of Health and Human Services -Food and Drug Administration- Department of Justice -Drug Enforcement Administration-
Process Drug discovery Drug design Drug development New drug application Investigational new drug Clinical trial (Phase I, II, III, IV) Randomized controlled trial Pharmacovigilance Abbreviated New Drug Application Fast track approval Off-label use
International coordination International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Uppsala Monitoring Centre World Health Organization Council for International Organizations of Medical Sciences Single Convention on Narcotic Drugs
Non-governmental organizations Institute of Medicine Research on Adverse Drug events And Reports
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Broadly the process can be divided into pre-clinical and clinical work.

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 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 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.

As this drug discovery process becomes more expensive it is becoming important to look at new ways to bring forward NCEs. One approach to improve efficiency is to recognize that there are many steps requiring different levels of experimentation. The early phase of drug discovery actually has components of real innovation, components of experimentation and components that involve set routines. This model of Innovation, Experimentation, and Commoditization ensures that new ways to do work are adopted continually. This model also allows the discipline to use appropriate internal and external resources for the right work.

Cost

Studies published by diMasi et al. in 2003 report an average pre-tax cost of approximately $800 million to bring a new drug (i.e. a drug with a new chemical entity) to market.^[1][2] A study published in 2006 estimates that costs vary from around $500 million to $2 billion depending on the therapy or the developing firm.^[3] 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.^[4] 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.^[5] A 2011 study also critical of the diMasi methods, puts average costs at $55 million.^[6][7]

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.^[8] 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.^[9]

See also

• Clinical trial
• Council for International Organizations of Medical Sciences
• Drug design
• Drug discovery
• Drug repositioning
• 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.
• Investigational New Drug, FDA application/permission to start clinical trials
• List of pharmaceutical companies
• Pre-clinical development

References

1. ^ DiMasi J (2002). "The value of improving the productivity of the drug development process: faster times and better decisions". Pharmacoeconomics 20 Suppl 3: 1–10. PMID 12457421. 
2. ^ DiMasi J, Hansen R, Grabowski H (2003). "The price of innovation: new estimates of drug development costs". J Health Econ 22 (2): 151–85. doi:10.1016/S0167-6296(02)00126-1. PMID 12606142. .
3. ^ Adams C, Brantner V (2006). "Estimating the cost of new drug development: is it really 802 million dollars?". Health Aff (Millwood) 25 (2): 420–8. doi:10.1377/hlthaff.25.2.420. PMID 16522582. 
4. ^ http://onlinelibrary.wiley.com/doi/10.1002/hec.1454/abstract
5. ^ The Truth About the Drug Companies (New York: Random House, 2004).
6. ^ http://www.palgrave-journals.com/biosoc/journal/vaop/ncurrent/index.html
7. ^ Noah, Timothy (2011-03-03). "The Make-Believe Billion: How drug companies exaggerate research costs to justify absurd profits". Slate. http://www.slate.com/id/2287227/. 
8. ^ Stratmann, Dr. H.G. (September 2010). Analog Science Fiction and Fact CXXX (9): 20. 
9. ^ "R&D costs are on the rise". Medical Marketing and Media. June 2003. 

External links

• Drug Development Technology Projects, companies and industry news
• CDER Drug and Biologic Approval Reports
• International Union of Basic and Clinical Pharmacology