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Clinical Research:Developing New Drugs

-Dr.Ravindra B Ghooi

The need for new drugs continues unabated, since there are still diseases that do not yield to available drugs. Additionally there are diseases against which existing drugs have poor efficacy or low safety. Lastly, as everyone knows, drugs are becoming more and more expensive; hence we need drugs that are more affordable. Through advances in medicine new drugs are required, each of them has to be deveoped through painstaking effort that takes over 12 years of time and over $1,500 million investment. Readers often confuse the meaning of the word – drug, in technical parlance a drug is what medicines are made of, and that is the meaning withwhich the word is used.

First step is discovery

The first step in drug development is discovery, i.e. the identification of an existing chemical or preparation of a new chemical that has biological properties. While most chemicals have biological effects, only those with a desirable effect (an effect that is medically useful) at safe doses will be taken up for further study. The next step is to study its effects on tissues or laboratory animals, to ascertain its principal biologic effect and if it has any effects on other systems that could contribute to its side effects. The drug will also be studied in depth to evaluate the mechanism of action, this has become essential now, since the innovators need to establish that before marketing the drug.

The safety testing of drugs is an important part of pre-clinical testing, in which its undesirable effects are explored. Some drugs are meant for single time use, while some are used for short durations like five days, there are also drugs which may be used for years together, like antidiabetic drugs. Each of these drugs will have to be tested for its safety when used for appropriate duration and often longer in animals. Past experience has shown that drugs given to a mother can have adverse effects on health, growth and development of the young one, hence extensive testing is done for its effects before, during and immediately after pregnancy. Testing protocols also include investigations for carcinogenic and mutagenic potential, too complex to be described here.

When a drug has been shown to be safe and effective in animals, then the final testing is done on human beings. There is great similarity between animals and man, hence the results obtained with animals tells us what may be expected in humans. Animals also differ from humans; hence one cannot rely totally on animal results and start using the drug on patients. Use in humans can only be initiated after it has been tested in humans for efficacy and safety. About animal testing, it must be mentioned that testing in animals is done very systematically, taking great care to protect animals from pain and suffering.

Clinical trials

The testing of drugs in humans is known as clinical research, and when new drugs are thus tested, they are known as clinical trials. Since these studies are conducted on humans, they need to be done in ethical manner, following the rules laid down by various organisations and countries. Drug research is highly regulated, and is second only to the aeronautical industry, in regulatory controls. Every institute involved in research has its own ethics committee that ensures that the human subjects of research are treated with utmost respect, dignity and follow national and international ethical codes. There are also a large number of rules framed by the regulators which ensure the safety of subjects and quality of data obtained.

Clinical trials are of various types and may use any one of the numerous designs available depending on the drug, the disease and the objectives of treatment. Trials are conducted in phases, with the higher phase following the lower. Before each phase, the data obtained till that point must be submitted to the regulator and permission sought for going further, additionally permission has to be obtained from the ethics committee before a single patient can be recruited for the study. Phase-wise testing in humans ensures that only the safest and most effective drug remains in the testing procedure and those not coming up to the standard get eliminated on the way. The first phase is to test whether the drug is safe for use at doses that are expected to  be used in patients. These doses are calculated from results of animal experiments. In a small group of healthy volunteers (not exceeding 80) the drug is administered, starting with very low doses, gradually building up the dose till the desired level is reached. Extreme caution is exercised throughout this phase, since it is the first time a human being is being exposed to the drug. To prepare for any eventuality this phase is usually conducted in centres with ICU facilities.

Focus on safety of drug

Single dose or repeat dose studies are conducted, depending upon the expected usage of the drug in therapy. During this phase, the absorption, metabolism, and elimination of the drug from the body are also studied. No extra effort is made to study what the drug does to the volunteer; indeed many drugs have no effects on healthy people, so this phase is focussed on the safety of the drug. This phase provides data on the basis of which, the second phase of testing is designed. At the end of the study a comprehensive report is prepared and submitted to the regulator for permission to conduct the second phase of study. Needless to say, if any problem is found to be caused by the drug it is promptly dropped from further development.

The second phase is often referred to proof of concept study, since the hypothesis that the new drug treats a particular disorder is tested. Obviously this phase is conducted on patients with the disease for which the drug is developed but preferably have no other complications. The total number of patients involved in this phase is higher than those in phase I, but rarely exceeds a few hundred. Using doses found to be effective in animals and those found safe in phase I, a dosage schedule is built for use in this group of patients.

The results of the study are carefully evaluated using statistical measures to assess the effect produced by the drug. These results help design the phase three of the trials. They help decide the dose, duration of the drug and the type of patients who are most likely to benefit from it. The drug is studied in this phase usually in comparison with a standard drug available for treatment. In special situations, where the disease under study has no current treatment, the new drug can be released for use based only on phase two studies, but this is rare.

 Method of drug use

The third and final phase of pre-marketing trials is the most critical for any drug. Here the type of patients used is similar to those seen in hospitals and clinics. They have the target disease, widely vary in age and weight and may have other complications too. Here the new drug is studied in comparison with the best available treatment in the country. Placebos (formulations without any active drug) were used com- monly in the past, but now their use is deemed unethical. A large variety of designs are used for this phase and the studies are usually multicentre, spread out over the country or all over the world. However the method of drug use and collection of data as defined in the trial protocol is identical, so that results from all studies can be pooled.

In this study, the patients and the physicians may be kept unaware of the identity of the drug individual patients are receiving (the new one or the standard one). The key to identity of drugs is a secret maintained in computers and files, so that this knowledge does not bias either the patients or the physicians. The allocation of the patients to either treatment groups is usually managed by computers, in a random manner so as to further reduce bias. For years, double blind, randomised studies have become the gold standard for clinical trials.

Watch on adverse effects

At the end of the study, only when the codes are broken and the data extracted, tabulated and analysed, does one know whether the new drug is better than the older one, and if so, how much better. Throughout the three phases a watch is kept on any adverse effects produced by the new drug, and now is the time to reconcile all the observed adverse effects with the observed benefits of the drug. Every aspect of life is associated with risks, so are new drugs. The question is, whether the benefits offered by the new drug offset its risk? The regulators analyse the data submitted and base their decision on the risk benefit ratio.

On the completion of this phase the sponsor (the company that has discovered the drug and conducted the trials) may request for permission to market the drug. It would supply every bit of data collected during the trials, including both adverse and beneficial effects of the drug, which would be reviewed by the regulators, over a period that may be as long as an year. Only when the regulator is satisfied that the risk benefit ratio of the drug is acceptable and that the drug offers some advantage over existing ones, a marketing permission would be granted.

The clinical phase of drug development consumes more than half the time and resources required to bring one drug to the market. This makes drug development one of the most risky and time consuming of pursuits. However, if the drug succeeds, then there is a pot of gold waiting at the end of the rainbow. Successful drugs have huge sales potential and quite a number of drugs have earned for their developers profits that have been many times higher  than the cost of development.

Unsafe; poor efficacy

As newer and safer drugs come to the market, it becomes clear that we have been using drugs that are quite unsafe, non-specific and have poor efficacy. With the entry of newer drugs, the cure rates for a variety of diseases have zoomed and patients are living a healthier and fuller life despite the disease. Even in diseases like cancer, cure rates are rising dramatically and patients are living more comfortably. The terrible adverse effects of cancer therapy are mostly a thing of the past and rarely do patients prefer death over treatment, as they did in the past.

In the last century, New Chemical Entities (NCE) dominated the pharmaceuticals market, but in this century biological agents have an upper hand. Of the ten top selling drugs in the world, seven are biological agents while only three are NCEs. This is a paradigm shift for the industry, bringing the focus back on biology from chemistry. Biological products are boosting profits of the industry, a necessity for greater investment in research.

India signed the WTO in 1994 and we became fully product patent compliant in 2005. Now our country has to develop the drugs its people needs, or pay the exorbitant prices the overseas companies charge for them. So far we have depended heavily on other countries to develop drugs for us, it is time we did it ourselves and if possible contribute to the health of the world by devel- oping new drugs. Indian scientists have demonstrated that they are second to none, and we must create an atmosphere conducive to testing the drugs they develop.

Outsourcing is popular

India is uniquely placed for clinical research in which outsourcing is a popular business model. We have the largest English speaking population of medical and para-medical experts, very well equipped hospitals and an innovative industry that competes with the developed world. For over a decade, India has been viewed favourably as a research destination. In the first decade, the industry showed an annualised growth of over 20%, only to fall later into depression. Bad publicity, unethical behaviour and sluggish regulatory mechanisms have cost the clinical research industry dear, but the industry is staging a comeback. It is hoped that good sense will prevail and the industry will be allowed to work without undue criticism.

Drug development and clinical research is an exciting field, which needs the best of brains. Unfortunately bad publicity, falling revenues and opportunities cause the brightest and the best to shun it. All over the world, clinical research is staffed by young bright persons; that is exactly what our industry needs. The health of future generations depends on new medical diag- nostics, techniques and drugs, and the only way to achieve it is through basic, preclinical and clinical research.

(The writer is director, Scientia Clinical

Services, Pune. He can be contacted at

ravindra.ghooi@gmail.com)