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

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.

Cost

The full of 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. 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.

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.

Novel initiatives to boost drug development

Novel initiaives include partnering between governmental organisations and industry. The worlds largest such initiative is the Inovative Medicines Initiative (IMI), and examples of major national initiatives are Top Institute Pharma in the Netherlands and Biopeople in Denmark.

While research and development aimed understanding, treating, and preventing disease is making progress at an ever-increasing rate, growth can be increased through grants from the government.

There are two major factors contributing to our attempts to eradicate disease: economic profit and altruism (pure or otherwise). As such, progress can be made by either increasing the relevant institutions’ potential for economic profit or by increasing the altruism of those participating (in terms of the goals of the institutions themselves and the individuals associated with them). Altruism can be increased through changing the worldviews held by those involved but, while there is potential for improvement in this area, progress is limited in large part because individual people almost universally haven’t reached their maximum capacity for contribution until we are adults, at which point our worldviews have been formulated and developed to such a degree that changing them would rely almost entirely on educational efforts. While changes in educational systems can still contribute to changing worldviews in favor of altruism and should certainly be used, it seems that creating economic incentives for the institutions and individuals involved would be a valuable means by which to contribute to disease-fighting efforts.

I propose that government grants can be used as a powerful tool to these ends, and that providing these incentives would constitute a trivial cost for the government when compared to its total budget. And, in any event, providing such incentives would require only minor changes with respect to the distribution of its budget and could even involve simply re-allocating some current healthcare expenditures. Additionally, the creation of powerful incentives would require very little legislative effort. I will now briefly outline one such incentive:

Institutions and the individuals comprising them will put more effort into fighting disease when each contributor sees the prospect of economic gain and, if the government increases competition, progress will occur at an increasing rate. Allocating $10 billion dollars for these grants—while to individuals this may seem like a lot of money, but it pales in comparison to America’s overall budget—to, say, the ten most valuable contributors (deciding how this will be measured will require further attention) each year, would provide a powerful incentive. As an example, our government could give out grants of $1 billion to each of the 10 companies it deems to have made the most progress in the last year. Each company would jump at the opportunity to secure these grants and, it must be noted, the winners of these grants would have more capacity for further contributions to disease-fighting efforts, creating the potential for a positive feedback loop.

I mentioned that providing this kind of funding wouldn’t require much legislative effort. This is because both Democrats and Republicans would want to create these grants as, the public would obviously benefit from increased disease fighting efforts and, as such, would ameliorate, to a certain degree, the public’s political unrest (in case you’re cynical about the intentions of our legislators, bear in mind that they would realize that such an effort would increase their chances of re-election).

The biggest remaining problem would be deciding not on whether grants should be created but, rather, how much money these grants should be worth and how many institutions will earn them. The public would also create pressure to have these changes go into effect as soon as possible, so the two parties would come to an agreement quickly, making the increase in progress begin almost immediately. And, consequentially, the quality of our healthcare would increase while, at the same time, reducing its cost.It amazes me that this kind of incentive for progress isn’t used by our government to a greater degree than it currently is.

As an extension of all this, I believe that applying this kind of incentive should be used in a broad range of other causes, in order to affect change. I’m amazed that we do this as infrequently as we do, and I know that we must use this tactic more frequently, across a wide variety of fields and pursuits.

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
• Biopeople

External links

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