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Drug Research: Chances and Risks Involved in the Development of New Drugs
Abstract: The development of a new drug is a mammoth project. It can take up to 15 years, involves hundreds of researchers, and costs several hundred million dollars. It begins with the process of finding a target in human body that causes a specific disease. In many cases these are proteins. Intellectual flexibility, team spirit and a willingness to learn are important factors for the successful research and Ravinder Kaul development of a new drug.

Introduction

Next to atomic and space research, development of drugs at the present time is the most expensive and demanding enterprise in the economy. The development of a new drug costs the companies 400 million dollars and in the world more than five thousand million dollars are set aside annually for this research. The companies carrying out this research calculate about 10 to 12 percent of their turnovers for these expenses. This cost is increasing and in the course of the last ten years alone has roughly quadrupled, the increase being due not only to higher costs of personnel and materials, but also to the more expensive trials and controls necessary in the light of the latest scientific knowledge as well as due to stricter new drugs laws and regulations. Unfortunately, this has not led to an increase in the yield of new drugs in the last 10 years but rather to a decrease. From whence then does the idea for a new drug come? What deliberations lead to new developments? How are ideas from chemistry and biology put into practise? What is the procedure for testing new drugs in animals and humans in order to arrive at the highest possible benefit for man under a maximum of safety, and finally what are the difficulties which may, right up to the last moment, cross the path of a new product and obstruct it? Unfortunately, it is only too rare that the theoretical ideas obtaining at the beginning of the development of a new drug later prove to be correct. Even today, chance too often has a hand in the game, chance in a scientific laboratory (penicillin, furosemide), in a chemical factory (prednisolone, streptomycin) or by the sickbed (oral antidiabetics, chlorpromazine). It is mostly

substances resulting from the chemists synthetic work or possibly also substances of interest from the point of view of patent rights that must be examined and tested for their hypothetical effect. But naturally a very important incentive in our research is the knowledge of a disease, of a medical indication for which there is still no effectively useful medicament available.

Simpler Concepts of Drug Discovery

The above observations and deliberations open up different approaches to new drugs: thus one may, for example, mix substances or extracts of plants or organs already known and proved in medicine, in prescribed dosages. Here the chance of producing an effective product is great, and the risk of encountering side effects or damage is small; one can take appropriate measures against known dangers. Naturally such plagiarism cannot be classified as a great scientific achievement in drug discovery, it contributes nothing new to therapy. The fixed combination of known substances or extracts in a mixture in proportions which are not at present available is more justifiable and medically often desirable. In these cases, in fact, the effect of the combination can generally be foreseen; the question remains open, however, whether the compulsory interplay of the individual components does not alter the toxicity in the body. Also, the proved effect of an individual component may be distorted through competitive influences. For this reason, new preparations created in this way must be subjected to a series of pharmacological and toxicological investigation, first to demonstrate the expected improvement in therapeutic effect and further to clarify toxicologically whether or not possible

* Dr. Kaul worked for German pharmaceutical company Robugen for 32 years, and is presently a consultant on plant medicine. He can be contacted at Im Hangelstein 27, 73730 Esslingen, Germany. Email: durgakaul@hotmail.com
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This short enumeration of the various possibilities shows that even in these research patterns different chances and risks are inherent in the individual routes. The chances of finding a new drug are naturally greatest with single substances from plant or organ extracts, where the extracts are already known to be effective. This is chiefly a matter of chemical and physical achievement, and the biological side is only concerned with the question of whether the pure drug offers any advantage over the extract in one or other direction. Similarly promising, but much more risky, is the chemical modification of substance known to be effective. Here, often the smallest alterations may make an active molecule still more effective, or perhaps even inactive or downright harmful. In these cases, therefore, what biology has to say on a drug will be decisive. The smallest chance and the greatest risk in the development of a new drug falls, however, to the lot of the one who does not cling to the known but starts in a completely new direction: namely research conducting enterprise! The development of a new drug is tied to two fundamental postulates: it must be effective, and thus be of benefit to the patient, and it must be safe to use, and thus be as free of risk as possible to the patient. I need not go any further into the details of the problem of chemical synthesis here but shall concentrate to the second decisive step in the development of a drug, biological testing. Here the biochemists, pharmacologists, toxicologists, bacteriologists and other work in close cooperation with doctors experienced in special fields. All newly developed substances and that is a large number every year are first of all sifted out by pharmacological screening; that is, they are put through a vast number of experimental procedures in specific dosages to see whether an effect emerges and where. If by this means evidence is obtained in favour of a particular direction of activity, the substance is then submitted to a more detailed analysis of its effects. In all these animal experiments, the question arises whether the results observed in animals can be transferred to humans. From years of experience it is known that certain animal tests are very informative as to how man will respond to a compound whose biological effects on him are unknown so far. Other tests only give a very rough indication. We use rats, cats, dogs, monkeys and every species we can find in the whole world that will perhaps help us predict to man. We do 10 days studies, 3 months, 6 months, 2 years and now in the Western countries they demand 8 to 12 years study of a drug in animals. This is 1/3 of a scientists life, a tremendous cost of time and money. Everyone

side effects of the individual components are intensified in the combination. The chances of producing a useful product by combining known drugs are naturally relatively great and the risks relatively small, particularly because the individual components are already well known and have possibly even been prescribed either alone or together for years by the doctor in his daily practice. Another way of producing a new drug with good chances and little risk is to try to catch the interest of the doctor and patient with a particular pharmaceutical form of preparation. Here the progress in our way of life often plays a great part. Meant here is particularly of the modern slow release and depot preparations which have become available in recent years, and which have enabled many products to be given in a single morning dose lasting the whole day. Such combination products or pharmaceutical improvements may be of therapeutical significance and medically desirable. If circumstances permit, they provide more comfortable and improved possibilities for treatment, occasionally there may be a price advantage. Therapeutically, they are practically, a kind of replacement for what the doctor and pharmacist used to provide by prescription and dispensing. The industry has taken over this field because it must keep a firm grip on the problem of effect and side effects arising from combination of several drugs. Also it believes that by the installation of modern machinery and manufacturing large amounts, it can best produce a reasonable and homogeneous product and best guarantee composition and stability by their system of checking both during and after manufacture.

Modern Drug Research

These above methods of drug development mentioned so far are certainly not those methods which would be considered to be real creative achievements in this field. Modern drug research also means new single compound with a progressive and a useful therapeutic effect. It may be done in one of the following ways: 1. by synthesizing completely new kinds of chemical substances, as it is primarily done in the laboratories of pharmaceutical research companies all over the world; by chemical modification of known substances with the object of bestowing new properties, for example, to increase its effectiveness or to render it less toxic, perhaps even to change its method of administration and finally; by the isolation and purification of active substances from biological, that is, plant or animal material.
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knows what the best test is but no one knows what it means to man. There is no evidence that any of these tests predict to man. One of the greatest problems in animal testing even today is that there are no animals as contract spontaneously or in which we can induce artificially those diseases we find in man when we come to use a drug. It is at this period of drug research that a great deal of experience, subtle intuition and a lot of luck are required actually to recognise the efficacy of a drug, to assess the effect correctly and to choose a compound which will act in man in the same intensity as in the animal tests. In spite of all these uncertainties, animal experiments will provide decisive evidence on: 1. 2. 3. the effect of a new substance and so its possible indications, possible accompanying effects and side effects and thus any possible contra-indications, the relationship of both desirable and undesirable effects to dosage and, therefore, of the therapeutically useful dosage, and the advance on the therapeutic substances previously available

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The second basic postulate for a new drug is its safety. That is as extensive a freedom as possible from undesirable side effects and harmful activity. These requirements make it clear that developments of drugs today is no longer complete without toxicological research. It is, so to speak, the conscience of drug research and may provide information on the limits of tolerance with regard to dosage, administration and length of treatment with a drug, and what damage can be expected from exceeding these limits. Various questions are of particular importance here: a) the therapeutic margin. b) the determination of kind and frequency of possible accompanying effects and side effects. c) the assessment of the dangers of incorrect use of the drug. d) the assessment of damage by the drug which might not appear during treatment, as for example carcinogenic or teratogenic effects. The toxicologist, therefore, has a particular responsible task in the development of the drug. The first basic foundation for assessment is the acute toxicity. It is usually done these days in cell cultures to get first hand information on its toxicity. For the completion of the assessment of a substance it is also necessary to know its sub-acute and chronic toxicity. A large number of constantly

repeated batteries of tests permit the determination during such tests of all the morphological and functional changes produced by the new substance as well as information on its metabolism and pharmacokinetic behaviour. Such a test series made for a single substance, for example, for a one-year investigation of chronic toxicity requires more than 10,000 tests on more than 400 rats and 40 dogs and cost more than 500.000 dollars. Finally, the toxicological assessment of a substance include test for teratogenicity, carcinogenicity, mutagenicity and multigeneration tests; all these are very popular additional studies now and new ones to come. Just as in the examination of the efficacy and possibility of indication of a new drug, the toxicological investigations of a new substance only give us rough indication of its real behaviour in man. The problem of transferability of results from animal experiments to man also applies here. With a compound like Isoniazid, the anti-tuberculosis drug, the original toxicity studies were done in dogs. It turns out that the dog cannot acetylate the compound .Now we know that man can acetlyate the compound. If it is given to monkey, it is found that the monkey is like man and acetylates the compound; the monkey gave the correct metabolic story. All the work that was done with the dog on Isoniazed was worthless; the dog was the wrong species for prediction to man. So in conducting the toxicity studies, it is very important to know the species of animals that shall metabolise the particular drug the same way as it does in man. All the toxicity and also pharmacological studies are to be done in those species of animals. Predictability of the right species is most important factor in drug research development in present days, that is, species that has the same metabolism as man and the same side effects. But there is no right was of predicting from animal to man. This uncertainty has already, justly and unjustly, held up the further development of many effective, useful, and progressive drugs and will do so in the future. This loss to progress is regrettable. Its extents depends largely on the significance and valuation of the respective finding and, hence, also on the scientific qualification and willingness of the people making the decisions to accept responsibility. For the company scientist and, therefore, for the industry, the risk in this situations is great that a wrong judgement may possibly bring to nought large investments, perhaps months or years of research as well as the hoped fruits of this work.

Additional Problems in Drug Development

However, problems and risks are not confined to the biological field alone, they also occur in the parallel spheres of biotechnological,
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For this reason, these preliminary test are never able to remove the risk from the first large scale use of a substance with any certainty. But it does give information on whether the possible therapeutically active dose inferred from the animal experiments is tolerated without reactions in man and whether completely unexpected symptoms do not appear. The next step is testing for clinical effectiveness in man. Here clinical pharmacology must establish the absorption, distribution (possibly inhibition of catabolism) and excretion of the new drug, and the clinician at the bedside must determine the range of activity depending on the dosage, and the careful observation of side effects. Therefore, immediately following the tolerance test a random clinical and therapeutic test is done which is to give information on whether the therapeutic effect expected as a result of animal experiments does in fact appear in man, and whether the new drug is comparable or superior to the already existing drugs. A true opinion of the value of a new drug, however, can be given only after a large scale clinical trial. This is always carried out by several clinicians, practising specialists, and if the indications permit general practitioners. The trial are now a days so planned that the results can be evaluated statistically and so provide widely confirmed statements on the effect of a drug and give information on whether the new compound produces marked side effects in addition to its main effect or produces habituation or addiction or whether by interaction with other drugs, it produces unexpected disadvantageous effects. The laymans desire for a completely harmless drug is Utopian. Every drug action is an intervention in the function and cell metabolism of the human body, and there is practically no drug if it really has any actions at all that may not produce side effects in same situation or other. The differences are only a matter of degree. There are drugs which very rarely produce side effects and others which more often may cause serious side effects. Whether a drug of the latter type should be used or not, is a decision for the doctor to make. He has to weigh the seriousness of the disease with the therapeutic methods previously available to him against the new therapeutic method with its accompanying effects. Such decisions depend on the particular case and cannot be fixed according to rigid rules. By describing the course of development of a new drug I have tried to show through how many stages a new substance must pass. In the various stages of investigations each compound is tested most thoroughly and only really effective and beneficial substances with justifiable risks get through the network of tests.

chemical and the pharmaceutical processing. The new drug must be presented in suitable forms for example tablets, ampoules, syrup etc. and the stability of these individual modes of application determined. These technical pharmaceutical problems are often quite big (for example size of crystals, isomerism, salt or base, water of crystallisation, viscosity, pH, coating and so on), and the search for the best physiological and pharmaceutically compatible preparation (bioavailability) is often of greater importance than generally assumed. A new substance is still far from an effective medicine and the preparation of one manufacturer is no way the same as the preparation with the same constituents of another manufacturer. Experience in daily practice provides many examples of this, thus refuting the frequently raised demands for the unreserved use of the generic name in the declaration and promotion. Difficulties may also arise in transferring the laboratory synthesis into production. A compound prepared in the laboratory sometimes may not be at all suitable for large scale production, or it may be that the laboratory method cannot be simplified, resulting in an uneconomical price of the active substance. A reliable method of analysis must also be found. Here, too there are uncertainties which reduce the chance of a product ever reaching the doctor.

Clinical Tests

After all these complicated and most of all time consuming investigations and tests, it is calculated that on the average a laboratory development period of about 4 to 5 years should allowed after the first synthesis all the questions which can only be answered by using the drug in man are till open. This phase requires a trustful and a responsible cooperation between doctor and industry, and is critical for the development of a new drug. It provides the answer to the question whether the effects obtained in animals are also valid for man and this alone decides whether the drug will be marketed or not. It is no rarity today that such clinical trial extends to 5,000 or even 10,000 patients and requires over 5 years. It follows a strict plan, the clinician having been provided with all the important information previously obtained giving him the assurance that the tests carried out so far give the greatest possible safety regarding dosage and tolerance of the new drug substance. This step from animal to man is full of risk. That may be stated quite frankly. It is, therefore, usual to test the tolerance of a new drug first of all. These preliminary tolerance tests are generally done in volunteers under strict medical supervision. Naturally this can only be done in a limited number of people.
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The modern methods of drug design are molecular modelling (quantitative structure-activity relationship QSAR; computer aided drug design CADD), combinatorial chemistry and so on. The question now arises as to how many efforts must be made to obtain in the end a therapeutically valuable preparation from a completely new single substance. I have investigated this question recently, and know that it is correct to say that at present time about 10,000 new compounds must be synthesised to obtain one therapeutically really useful new single drug preparation. This ratio can of course be improved to 1:5000 or 1:4000, if one does not search for a completely new compound with a new mode of action, but alters an already known molecule or even combines substance known to be effective, or produce a new pharmaceutical form of known drugs. In such case the chances of finding new product are naturally greater and the expense for the whole range of development is considerably less. In the development of a new single agent with a new mode of action, one must then start into the idea that today at least 10,000 compounds must be synthesized and tested. Of these, only about 1,500 survive the screening test, and of these 1,500 only about 100 or so pass the deeper biological tests. About 10 compounds still remain after these 100 biologically active substances have been examined toxicologically. For reasons of pharmaceutical processing or biotechnology, analysis and development of chemical methods, another 2 fall out, another 1 in the tolerance test in man, about 3 in the preliminary random therapeutic tests and another 3 in the large scale clinical trials, so that finally only 1 substance remains to become a useable drug.

substances from which not only one, but possibly even several new therapeutically valuable drugs can be developed. The history of pharmaceutical industry even at the present time shows that it is absolutely possible, even with a limited research budget to achieve real progress. But just as well one must recognise that even a large firm with a large research budget may possibly achieve no useful result for years. Then often several times 10,000 compounds have been synthesized and tested without success, and the development of one final product may cost this firm considerably more than 400 million dollars.

Patent Laws and Other Risks

One cannot hide the fact that in the development of new drugs, the chances are small, the risks great and the costs high. This statement is still more meaningful if one bears in mind that a company is never alone, but competitors search, develop and imitate. It may happen that all tests and results have gone favourably for your product; the problems of price and marketing are satisfactorily solved, but one then finds out that a competitor has been working in the same field and has patented his product earlier or can market it earlier. In such cases one must break off

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Cost of Development of a New Drug?

What does such development procedure cost? Today one can reckon on that the development and testing of a new effective drug costs easily over 400 million dollar! Of this about 30% are spent in the field of chemistry, 45% goes to the experimental medicine research laboratories and about 10% for the clinical development, 10% for the pharmaceutical or biotechnology, analysis and development of chemical processes and about 5% for documentation, research into literature and general expenses. Naturally, not every new product needs a direct expenditure for 400 million dollar, otherwise medium sized and small firms with limited research capacity could never have any success. Sometimes a firm has luck on its side for once, and astonishing rapidly hits on a new substance, or even discovers a group of

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In the genes researchers look for faults in healthy and ill people that could trigger or promote a disease

In the cells researchers observe the behaviour of the proteins and examine metabolic disorders in diseased cells

In scientific journals researchers find important tips and information for their work

When the researchers find a target (for example. a protein), they study its threedimensional structure, chemical characteristics and function

A library of substance that may affect the target protein is compiled

A screening robot tests the substances - often many hundreds of thousands of them - on the target protein. If the two bind, this is indicated by a signal (such as a colour reaction)

In the lab and using computer models of the target protein, the selected substances are chemically altered to improve their effect
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Model systems show whether the body absorbs the substances and if they reach the target protein or cause side effects

The variants are run through a large number of tests. Step by step, unsuitable substances are eliminated

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In the end, one substance is left that binds to the target protein best and has the best chances of positively influencing the course of the disease

The substance is administered to animals. If it has no effect or there are doubts about its safety, the substance is eliminated at this stage

10 At the same time, scientists consider the best way to administer the substance as a drug: in tablet, capsule or liquid form

If the animal test results allow, clinical trials begin

11 In Phase I physicians tests the drugs safety on healthy volunteers and determine proper dosage

12 In Phase II effectiveness is tested on a smaller number of patients

13 In Phase III Physicians test the drug on a large number of patients

14 The clinical trials are followed by the approval process. Independent experts examine the data complied by the manufacturer and decide Whether the drug is safe and has the desired effect

15 Large-scale production begins as soon as approval is granted

16 The new drug is made available to patients

The Long Road to the Finished Medication (picture source Future The Aventis Magazine 1/2004)
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accompanying effects. The constantly increasing expenses in recent years in research in the pharmaceutical industry are not only due to the development of new products, but also due to maintenance, advancement and consolidation of specialities which have often been on the market for many years.

the further development of a substance at a very late stage or withdraw shortly before introduction of the product. All expenses then are lost. Every pharmaceutical company particularly because of the exceedingly long development period also runs the risk of developing a product which, when it is finished, is really obsolete from the point of view of chemical technique or medical science, or is not successful for one reason or another in spite of all the previous market research and morbidity statistics. A further risk affects the period after the introduction of the product. Here every drug manufacturer is faced with the fact that the results of every good, exact and far reaching clinical trial must be confirmed by the extensive use of drug in practice. Everybody knows that in clinical trials a new drug in the trial stage is used under strict control, that the patients are specially chosen, their number limited and they remain under supervision. This is quite different from conditions in general practice. Here the doctor no longer has the patients so firmly under control. The patients environments, the dosage, the time of administration and many other things vary, perhaps even daily, and deviate from the conditions of clinical trial. This situation may lead to considerable departure from rigid conditions of use in the clinic and, therefore, to changes in the effect and also side effects of the new product. Possibly, suddenly, harmful effects may be attributed to a valuable new product, which are not present in proper therapeutic use. On the other hand, very rare side effects which have not been seen during the animal experiments may be observed only after use in 100,000 or 1 million cases, that is, after a number of cases which would be absolutely impracticable for a clinical trial (for example thalidomide, aminorex etc.). Moreover, today the industry constantly runs risk with their old and new products that scientific investigation intended to establish possible harmful effects will be falsely interpreted, the results perhaps even wrongly understood and interpreted by the daily press and that then an unwarranted unrest is created in the relationship drug, doctor, patient (for example antidiabetic, cyclamate affair, ovulation inhibitors etc.). From what has just been said it is clear that drug research today can no longer confine itself to developing new methods of treatment and to creating new, perhaps life saving drugs, but that it also has the duty to confirm and support past discoveries. In many cases this research task is just as expensive as the search for a new product. This does not only involve the control of quality and stability of the drug introduced, but above all the safeguarding of effects and tolerance and the clarification of possible harmful
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Ethical Arguments of Drug Research

If today the question arises whether it is good for ethical reasons or on grounds of social and health politics to pursue drug research the answer to this is certainly `Yes`. The costs of developing a new drug are low in comparison to those generated by the illness it is designed to alleviate. For instance, according to American Heart Association, a cardiovascular disease in the United States costs the country 300 billion dollars in 2001. This includes direct costs of treatment and indirect costs for loss of productivity resulting from illness and health. Hospitalization accounted for 65% of the direct costs of 182 billion dollars. In contrast, only 15% of this sum went to medication. One logical deduction is that every new drug that shortens or even prevents hospitalization must make a substantial contribution to lowering direct medical costs as a whole. This is especially true of prophylactic drugs, such as those used to reduce the risk of thrombosis. From the manufacturer point of view one can agree to this way with reservations. This is all the more so since a widening of certain tendencies in the field of patent protection would mean reduced or completely removed protection of intellectual property, and , therefore, a substantial impulse of drug development would be lost and the economic risk involved would be increased to an irresponsible extent.

Conclusion
Now I have certainly described in considerable detail how a new drug comes into being, what risks industry has to face and what industry does to place at the doctors disposal only those products which are of great benefit to the patient and as free of risk as possible. In India, the progress in drug research and in the supply of drugs is only assured in the future with the protection of intellectual property and the retention of scientific and economic freedom. It is however, important that workers in industry, the doctors at the bedside, the scientist in the university and in the state organisations and health politicians in India always remember this constantly necessary advance, and work together with mutual understanding for that progress that shall lead our country to a sound professional and economic goal.