Chapter 3 Discovery and development of drugs
• Preclinical drug development. Discovery of new drugs in the laboratory is an exercise in prediction. Selecting the target for a drug is probably the key decision.
• Techniques of discovery. Several approaches, including using small molecules, large proteins and nucleic-based approaches, broaden what we think of as a medicine.
• Studies in animals. Some are required by regulation (for safety), others give insight into the effect of the drug in the whole body, but none replaces the need for clinical testing.
• Experimental medicine. Getting the medicine into the clinic to test its properties and its effects on biological systems is a key step.
• Prediction. Failures of prediction occur and a drug may be abandoned at any stage, including after marketing. New drug development is a colossally expensive and commercially driven activity.
Making a new medicine
1. Selecting the molecular target you want the drug to act on to produce the desired effect.
2. Choosing the right chemical as the drug candidate. All the promise and all the faults become fixed at this point.
3. Designing the right clinical experiment to show that the medicine will really do what you want it to do.
Medicinal therapeutics rests on the two great supporting pillars of pharmacology:
1. Selectivity – the desired effect alone is obtained: ‘We must learn to aim, learn to aim with chemical substances’ (Paul Ehrlich).1
2. Dose – ‘The dose alone decides that something is no poison’ (Paracelsus).2
The huge increase in understanding of molecular signalling – both between cells and within cells – has opened many new opportunities to develop medicines that can target discrete steps in the body’s elaborate pathways of chemical reactions.3 The challenge, of course, is to do so in a way that produces benefit without harm. The more fundamental the pathway targeted the more likely there is to be a big effect, whether beneficial, harmful or both. No benefit comes without some risk.
1. More potential drugs and therapeutic targets were identified that could be experimentally validated in animals and humans. This ‘production line’ approach also led to a loss of integration of the established specialities (chemistry, biochemistry, pharmacology) and to an overall lack of understanding of how physiological and pathophysiological processes contribute to the interaction of drug and disease.
2. Theoretically, new drugs could be targeted at selected groups of patients based on their genetic make-up. This concept of ‘the right medicine for the right patient’ is the basis of pharmacogenetics (see p. 106), the genetically determined variability in drug response.
Pharmacogenetics has gained momentum from recent advances in molecular genetics and genome sequencing, due to:
• rapid screening for gene variants
• knowledge of the genetic sequences of target genes such as those coding for enzymes, ion channels, and other receptor types involved in drug response.
• The identification of subgroups of patients with a disease or syndrome based on their genotype. The most extreme of obvious examples of this are diseases caused by single gene defects. The ability accurately to subclassify based on common genetic variation is less clear.
• Targeting of specific drugs for patients with specific gene variants. This is most advanced in the field of cancer (usually targeting somatic changes in cancers) and increasingly in the field of the pharmacogenetics of safety (i.e. unwanted drug effects).
Consequences of these expectations include: smaller clinical trial programmes with well-defined patient groups (based on phenotypic and genotypic characterisation), better understanding of the pharmacokinetics and dynamics according to genetic variation, and improved monitoring of adverse events after marketing.
New drug development proceeds thus:
• Idea or hypothesis. ‘This protein causes this disease/these effects which I could stop by affecting protein function.’
• Design and synthesis of substances. ‘This molecule produces the wanted effect on protein function and has the physico-chemical characteristics that make it a potential medicine.’
• Studies on tissues and whole animal (preclinical studies). ‘When I test it in appropriate models it does what I expect and that allows me to believe it would do the same in humans.’
• Studies in humans (clinical studies) (see Ch. 4). ‘Initially I want to know whether the molecule has drug-like properties in terms of its kinetics. I then want to know that it does what I need it to do in terms of the effect on disease.’
• Granting of an official licence to make therapeutic claims and to sell (see Ch. 6). ‘Is my medicine better than than placebo? Does it do more than existing medicines and is it well tolerated.’
• Post-licensing (marketing) studies of safety and comparisons with other medicines. ‘Now many thousands of patients have taken it, am I still sure that it is safe.’
The (critical) phase of progress from the laboratory to humans is often termed translational science or experimental medicine. It was defined as ‘the application of biomedical research (pre-clinical and clinical), conducted to support drug development, which aids in the identification of the appropriate patient for treatment (patient selection), the correct dose and schedule to be tested in the clinic (dosing regimen) and the best disease in which to test a potential agent’.4
It will be obvious from the account that follows that drug development is an extremely arduous, highly technical and enormously expensive operation. Successful developments (1% of compounds that proceed to full test eventually become licensed medicines) must carry the cost of the failures (99%).5 It is also obvious that such programmes are likely to be carried to completion only when the organisations and the individuals within them are motivated overall by the challenge to succeed and to serve society, as well as to make money. A previous edition of this chapter included a quote from a paper I wrote from my time in academia and I leave it here:
Let us get one thing straight: the drug industry works within a system that demands it makes a profit to satisfy shareholders. Indeed, it has a fiduciary6 duty to do so. The best way to make a lot of money is to invent a drug that produces a dramatically beneficial clinical effect, is far more effective than existing options, and has few unwanted effects. Unfortunately most drugs fall short of this ideal.7
