Developing safe and effective drugs is a process that should include an understanding of clinical, legal, and regulatory matters.
New drug development has revolutionized the practice of medicine, converting many once fatal or debilitating diseases into almost routine therapeutic exercises. For example, deaths from cardiovascular disease and stroke have decreased by more than 50 % in the USA over the past 30 years. This decline is due in part to the discovery and increased use of anti hypertensive, cholesterol synthesis inhibitors, and drugs that prevent or dissolve blood clots. The process of drug discovery and development ahs been greatly affected by investment in new technology and by governmental support of medical research.
In most countries, the testing of therapeutic agents is now regulated by legislation and closely monitored by governmental agencies. This chapter summarizes the process by which new drugs are discovered, developed and regulated. While the examples used reflects the experience in the USA, the pathway of new drug development is generally the same world wide.
One of the first steps in the development of a new drug is the discovery or synthesis of a potential new drug molecule and correlating this molecule with an appropriate biologic target. Repeated application of this approach leads to this compounds with increased potency and selectivity. By law, the safety and efficacy of drugs must be defined before they are marketed.
In addition to in vitro studies, most of the biologic effects of the molecule must be characterized in animals before human drug trial can be started. Human testing must then go forward in three conventional phases before the drug can be considered for approval for general use. A fourth phase of data gathering and safety monitoring follows after approval for general use.
Enormous costs, from $150 million to over to over $800 million, are involved in the research and development of a single successful new drug. Thousands of compounds may be synthesized and hundreds of thousands tested from existing libraries of compounds for each successful new drug that reaches the market. It is primarily because of the economic investment and risks involved as well as the need for multiple inter disciplinary technologies that most new drugs are developed in pharmaceutical companies. At the same time, the incentives to succeed in drug development are equally enormous. The world wide market for ethical (prescription) pharmaceutical in 2001 was $ 364 billion. Moreover it has been estimated that during the second half of 20th century, medications produced by the pharmaceutical industry saved more than 1.5 million lives and $140 billion in the cost of treatment for tuberculosis, poliomyelitis, coronary artery disease and cerebrovascular disease alone. In the USA, approximately 10% of the health care dollar is presently spent on prescription drugs.
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, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together these processes are known in preclinical development as CMC: Chemistry, Manufacturing and Control.
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 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. 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.
Most new drug candidates are launched through one or more of five approaches:
1. Identification or elucidation of a new drug target
2. Rational drug design based on an understanding of biologic mechanisms, drug receptor structure, and drug structure.
3. Chemical modification of a known molecule
4. Screening for biologic activity of large number of natural products; banks of previously discovered chemical entities; and large libraries of peptides, nucleic acid and other organic molecules
5. Biotechnology and cloning using genes to produce larger peptides and proteins. Moreover, automation, miniaturization and informatics have facilitated the process known as “high through-put screening” which permits millions of assays per month.
Major attention is now being given to the discovery of entirely new targets for drug therapy. These targets are emerging from studies with genomics, proteomics and molecular pharmacology and are expected to increase the number of useful biologic or disease targets ten-fold and thus be a positive driver for new and improved drugs.
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed.
In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. A new approach has been to understand how disease and infection are controlled at the molecular and physiological level and to target specific entities based on this knowledge.
The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has shown its value in these tests, it will begin the process of drug development prior to clinical trials.
Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, “expensive, difficult, and inefficient process” with low rate of new therapeutic discovery. Currently, the research and development cost of each new molecular entity (NME) is approximately US$1.8 billion.
Information on the human genome, its sequence and what it encodes has been hailed as a potential windfall for drug discovery, promising to virtually eliminate the bottleneck in therapeutic targets that has been one limiting factor on the rate of therapeutic discovery. However, data indicates that “new targets” as opposed to “established targets” are more prone to drug discovery project failure in general. This data corroborates some thinking underlying a pharmaceutical industry trend beginning at the turn of the twenty-first century and continuing today which finds more risk aversion in target selection among multi-national pharmaceutical companies.