Developing a new drug
Generally it takes around ten years and costs up to €100 million or more to develop a new drug from a promising chemical substance. This is why pharmaceutical industries often are very large companies.
The first step (Chemistry in the figure) is to identify one or more potential candidates for drug development, i.e., substances that have good medicinal effects and can possibly be made into drugs. There are various ways of finding interesting candidates for drug development. One way is known as screening. In other words, one designs a pharmacological test in which one examines a lot of substances, plant extracts or something else. When you get a positive effect from the test you have a potential candidate for medical use and the developmental stage can start.
The second phase is the detailed pharmacological studies which involve learning more about how the substance affects the body. You also carry out toxicological trials to determine whether the substance is toxic for human beings at low doses. In addition tests are made to examine the effect of the product on the foetus in pregnant animals. Then, too, there are the pharmacokinetic studies on the substance, i.e., how the body affects the substance, e.g., if the human enzyme system breaks down the substance or if it is excreted in an unchanged form. At the same time, an industrial process is developed so that the drug can be manufactured if it gains approval.
After this, the national agency for medical products checks the documented results in order to decide if the positive effects of the substance outweigh possible negative ones and that the product is not dangerous for human beings. There may still be adverse effects but only such that do not cause permanent damage. If the authorities approve, then it is time for the next stage in the development. But if they aren’t completely satisfied then further tests must be carried out before the product is approved for clinical trials.
The word clinical is used since the new tests will be carried out in clinics, i.e., by a physician on living patients. The first stage is phase I of the clinical trials, which involves giving the substance to healthy volunteers to see if the medicine has any adverse side effects. The study is carried out on 20-50 people and the dose is increased successively during the trial. Blood samples are taken from the volunteers for pharmacokinetic testing. At the same time more toxicological studies are made on animals to ensure that there are no damaging effects. These may well be tests where animals are given the drug over a long period to see, for example, if they develop cancer.
The next stage is the second phase of the clinical trials where the product is tested on voluntary patients who suffer from the illness that the drug is designed to treat. This is a larger group consisting of 50 to 100 patients being examined. At this stage it can be determined what amount of the drug is needed to produce a good effect and if tolerance is developed, i.e., if higher and higher doses are needed to achieve the same effect during the course of treatment.
Then comes phase III of the trials which involves a large number of patients (500-5 000) being treated with the drug at which time it is compared to previously approved medicines. By now it is known what dose should be given and how it should be administered, i.e., the form of the drug, e.g., tablets or a solution. It is also known what adverse effects can be expected and there is an industrial process in place for production of the drug. Then an application is made to get the drug registered and if all the results are good, if the drug is effective and sufficiently harmless, it will be approved and may be sold as a drug. Even after gaining approval, further scientific trials on the drug are carried out.
In order to have sole right to the invention – the drug – it must be patented. Then nobody is allowed to manufacture and sell the same thing. The patent for a drug lasts 15 years and during that time the company must earn enough money to cover the costs for developing the substance and enable the search to go on for new substances which may eventually become new drugs. For every successful drug there are many that fall before reaching the finishing line, i.e., gaining official approval. As soon as the patent lapses, there are companies that make copies of the drug and produce cheaper medicines since such companies have not had the high development costs.
Pharmacological tests are used when one wants to evaluate if a substance or plant extract is biologically active. There are many pharmacological tests and each one of them demonstrates various aspects that are important for the understanding of the mechanisms behind illnesses, their causes and cures. When people talk about pharmacological tests they often think about tests on animals, but in fact these form only a small part of all such tests. One can determine if a substance has an effect on isolated enzymes as well as human or animal cells by using a test tube. For instance, products for treating cancer are first examined in test tubes on cultivated cancer cells from tumours and only if they have a good effect are they then tested on other systems.
Unfortunately it isn’t possible to develop drugs without using any animal testing at all, since the absorption and decomposition as well as any damaging effects must be studied in a whole organism in order to give a correct picture. The various organs in the body influence the drug and are affected differently by the drug and this involves, among other things, the risk of missing damaging effects caused by the drug directly or indirectly via products of decomposition. On the other hand one can minimise the number of animals in drug development and ensure good conditions for those animals that are used. Ethical codes concerning laboratory animals are important in ensuring that animals are treated well.
To avoid harming human beings, various toxicological tests are made to detect possibly dangerous side effects. These can either be test tube experiments, for instance when cultivated human liver cells are tested for adverse effects from a certain substance, or animal experiments where, for example, tests are performed to try to establish effects on various organs.
First and foremost, test tube experiments are used to determine if the substance affects the cells from different human organs. It also possible to see if the substance damages the gene pool or could cause cancer. If the substance shows no dangerous effects in these tests, then further testing is carried out on animals.
Most drugs affect not only the body but are in turn affected by the body. The body’s organs break down the drug into various metabolites – these are the products of the degradation process which are chemically related to the drug. This means that the body is affected differently depending on how long the product remains in the body. The metabolites can also have medicinal effects. The study of how fast and in which ways a drug is both absorbed into, and excreted from the body, is called pharmacokinetics.
If you are given an injection, the medicine is injected directly into the bloodstream and the drug begins its work almost immediately. On the other hand if you take a pill, this has to first find its way down into the stomach and be dissolved before the body can absorb it through the mucous membrane of the stomach. For this reason it takes a while before the concentration of the drug is sufficiently high in the blood for it to have a medicinal effect. It takes about a quarter of an hour before the active ingredient of a headache pill gets into the bloodstream and can begin to fight the headache. Nevertheless you often feel better almost immediately after taking the pill. This is called a placebo effect – the effect of an expectation. You feel better just because you have taken the medicine and not because the medicine has begun to work. The effects of drugs are often compared to the effects of a placebo, e.g., sugar pills that contain no medically active substances.
Drugs or herbal remedies?
There are several concepts within the area of medicinal plants where confusion is likely. One such instance concerns legislation whereas others are purely practical.
They all have their origins in nature – either plants, animals or minerals. They can be pure chemical substances, or mixtures of several, as long as they are all natural. Examples within medicine and medicinal plants are camomile flowers, valerian roots or morphine and nicotine.
These are products covered by pharmaceutical legislation, i.e., something that will cure, relieve or prevent illness, as well as certain diagnostic aids. They can be herb teas, plant substances or synthetic chemicals that are used for the treatment or prevention of illness.
This is a sub-group of medicinal products, and it is important to note, that in Sweden, according to the law, they are classed as medical drugs. They are products that may be used for self-treatment, i.e., mild ailments that don’t require the intervention of a physician. The group includes less refined natural products, e.g., herb teas and plant extracts but not pure chemical substances from natural sources. They have no guaranteed medicinal effect but are considered to be harmless when used sparingly. The dividing point between them and food products or dietary supplements can sometimes be unclear. Most significantly, maybe, is that herbal remedies are recommended by the producer for use in connection with certain ailments.
Dietary supplements are covered by legislation concerning foodstuffs and not by pharmaceutical legislation. Supplements to the daily diet can be plant extracts, minerals or vitamins. It is of importance that nothing on the packaging indicates that they can be used for treating or relieving any illness.
Recently the concept of functional foods has been discussed widely, i.e., eating something as a preventive measure or for its medicinal effects on an illness. This is still a young branch of medicine but a lot of research is being done in this field. It’s not just a matter of immediate replacement in cases of deficiency diseases. If you don’t eat vitamin C you are liable to get scurvy or if you don’t eat enough protein you will get kwashiorkor. For example it has been demonstrated that certain inflammatory diseases are improved when the patient eats oily fish. A diet high in fibres can counteract cancer of the large intestine. The significance is that it is all the more important to eat a varied diet.
Bruhn, J G 1990. Naturmedel – en läkemedelsgrupp som växer. s. 99-106 ur Naturliga läkemedel. (red. J G Bruhn), Apotekarsocietetens förlag, Stockholm.
Rudérus, H 1992. Funktionella livsmedel – sega gubbar eller mat för segare gubbar? Kemisk Tidskrift 11:24-26.
Comparing old-fashioned medicines and modern health food
Many of the plants sold in modern health food shops as natural health products, herbal remedies or health foods, are still or were once used in western school medicine. Here are some examples of such plants: arnica, birch leaf, bilberry, glossy buckthorn, yellow gentian, camomile, hops, milk thistle, senna, and valerian. The new big-selling plants ginkgo, ginseng and echinaceas, on the other hand, have entered the Swedish medical system in the past decades.
Many natural products and health food producers, as well as health food shops in Sweden, are affiliated to The Swedish Health Food Council which teaches, informs and disseminates knowledge about health foods, natural products and alternative medicine.
The formulation of drugs
A drug can have many different forms depending upon how it is manufactured, to be taken or the desired effect. The most common forms of drugs are tablets or solutions. The solutions can be made either to be taken orally, like cough medicine, or injected, as in the case of insulin. Eye drops are solutions that are administered directly into the eye.
A tablet can be manufactured in different ways depending on its intended purpose. A tablet can be made soft, to be dissolved in the mouth, or really hard so that it doesn’t break up before reaching the intestines, i.e., after passing through the acids in the stomach. Certain headache or vitamin products are in the form of effervescent tablets.
The classic form for a drug is the pill, a soft, pea-sized ball containing the drug and taken orally. Pharmacists used to roll them by hand. Nowadays pills, or tablets as they are also called, are manufactured in machines and consist of powders that are pressed together to form a compact mass.
Drugs can be taken orally, i.e. through the mouth (tablets, capsules, solutions), injected into the body (solutions), inhaled (powders and solutions), through the skin (ointments, creams and certain plasters), drops applied locally in the eye or ear (solutions) or inserted into the anus (suppositories) or the vagina (vaginal suppositories).
In Linnaeus’ time there were other forms of drugs that in school medicine we more seldom use today, for example solutions such as decocts (when for instance a plant is boiled in water), infusions (the same method as we use when making tea), and tinctures (extracts made with alcohol). They also used preserves (plant parts pounded together with equal amounts of sugar) and confections (ill-tasting plant parts covered in sugar to make them palatable). In modern usage the concept confection has been taken over by the industry producing sweets and candy. The modern way of manufacturing tablets wasn’t invented until the 1840s.