by Dr. Kalindi Phadke
When our doctor prescribes a new medication for our lingering disease, we are awed by the sky high price of that drug. We wonder how a common man can afford to pay for such prescription and why the price of such a tiny pil should be so high.
How many of us give a thought to what goes on behind the screen before such pill arrives in the market ? I had a good fortune to be associated with a giant pharmaceutical company in the United Sates for a number of years as a scientist, and had an opportunity to witness and participate in developing new and novel allopathic drugs. I would like to share with you the gargantuan and mind- boggling effort that is invested in such an endeavor.
These drug houses in U.S.A. generate tremendous profits by marketing drugs and have to pay heavy taxes to the government. If they spend a part of these profits on research & development ( R&D ), the expenses for such efforts are tax deductable. Furthermore, the R&D activities are the basis for development of new drugs and therefore more profits ! The major drug companies in U.S.A. spend millions of dollars every year on R&D.
The R&D subsidiary company employees many researchers with different backgrounds. Chemists, biologists, biochemists, pharmacologists, pharmacists, toxicologists, medical doctors, veterinarians, statisticians, computer scientists, etc. work together on various projects. They have access to fully equipped and ultramodern laboratories, animal houses, animal farms and hospital. More emphasis is generally given on common ailments, such as heart diseases, stroke, brain disorders, arthritis, osteoporosis, diabetes, asthma and emphysema, and development of new and novel antibiotics. The market survey department furnishes information on number of patients suffering from a particular disease and the number of prescriptions written by doctors in USA and all over the world.
The research starts at very basic levels. The chemists synthesize different chemical compounds belonging to various structural categories. The biologists and biochemists make “models” to mimic the disease process in to or in parts. The disease similar to that in humans is created in small animals. Also, if the pathway of progression of the disease is known, parts of that pathway are reproduced in animals, or in the laboratory at cellular, sub cellular or tissue level. The compounds synthesized by the chemists are tested in these different “models” at various doses. If any of them shows significant activity in suppressing the disease or any part of it, the structure of that compound is altered in many ways by chemical reactions and the activity retested, thereby establishing the structure activity relationship for that series. The compounds showing slightly less activity are reserved as “back up” candidates. A quick study is done on the toxic effects of the most active compound at high doses on rats or mice.
Once a compound is identified as a possible future drug, an application is made to the Federal Drug Agency ( FDA ) for introduction of new drug or IND, citing all the data on activity of that compound in test models. FDA has a major job of watching and scrutinizing every detail of such application. Main aim of the drug companies is to make
profits by marketing new drugs, while FDA is highly concerned about guarding the safety and interests of the common man. It is but natural that the drug makers and FDA are at times suspicious and at odds with each other. The drug makers tend to ignore minor side effects of the drug, while sometimes FDA can be too critical in its point of view. Once the IND application is passed, a project team for that compound is formed within the drug company, consisting of scientists with different specialties. From this point onwards, all the data generated on that compound are to be properly recorded and made available to the FDA. The compound is given a serial number and here onwards is known by that number. The information regarding the structure and activity of that compound are kept as closely guarded secrets to avoid any future problems of leaking such vital information to the other drug companies.
At this stage, the active compound is subjected to rigorous and thorough testing in various ways. Short term and long term toxicology studies commence using two small animal species, such as mice, rats, guinea pigs or rabbits and two large animal species, such as dogs, sheep or monkeys. It is observed whether the compound is carcinogenic, i.e. produces cancer of any type, or causes genetic defects in the progeny of small animals. Concurrently, drug metabolism studies are undertaken, i.e. the time required for absorption of the compound from stomach of the animals, the form in which it is carried to the blood, duration to achieve maximum blood levels, the rate of degradation of the compound, analysis of the metabolic products, excretion pathway(s), and whether the compound gets deposited in any tissue and if so, adverse effects of such deposition over time. Simultaneously, the pharmacists make proper formulation of the compound as a liquid, tablet, capsule, aerosol preparation or injectable, so that it is easily absorbed in the body. According to the activity profiles, the compound is formulated in large batches.
Once the project team satisfies itself about the excellent activity and low or negligible toxicity, a “new drug application” (NDA ) is made to the FDA. With its approval, the compound turned into potential new drug is administered to a small group of carefully selected patients, under the strict supervision of company doctors. Once these data on humans are approved by FDA, a sizable group of patients is subjected to blind studies. One group of patients is treated with the drug and the other with a similar formulation in appearance, but devoid of drug,i.e. placebo. The doctors in charge and the patients do not have the knowledge of which group is receiving what. If the results show that the drug is effective for the disease, double blind studies are undertaken. The group receiving placebo is treated with the drug and that treated with the drug receives placebo. These are sure fire tests for assessing the real activity of the drug, eliminating all types of psychological barriers in the minds of patients as well as doctors. All the data have to be statistically evaluated and found significant. Any toxicity, not previously seen in animals, but observed in humans cannot be ignored. Blood sera, urine and faeces of patients are analysed frequently. The patients periodically undergo many other test procedures, such as X- rays, sonography, MRIs, etc.
All the data generated on patients, including efficacy, toxicity, metabolism, etc, etc are submitted to the FDA. If everything passes the scrutiny of FDA scientists, multicentre trials commence in U.S.A. and sometimes abroad. The drug is tested on a large number of patients from a variety of population segments in terms of age, sex, race, severity of the disease, etc. The drug and the protocol of treatment, approved by FDA, are provided to these hospitals. Only after obtaining favorable results with patients in these trials the drug enters the market. The accompanying literature must include the chemical structure of the drug, route of administration, dosage, metabolic data and side effects. Clear warnings have to be posted if the drug is carcinogenic or teratogenic at high doses or after long term usage, and deleterious effects, if any, on pregnant women, lactating mothers, infants and children.
In spite of all the pretesting and precautions, unexpected and unacceptable toxic effects of the drug may be reported and it has to be withdrawn from the market. The comparison of efficacy dose and toxicity dose is extremely important in cases of chronic diseases, where patients have to be treated with the drug over a long time period. If the drug is not rapidly metabolized and is deposited in some internal organs for considerable time, this can create problems.
When a new drug with novel mechanism of action is marketed, the drug makers earn tremendous profits. The other companies then follow by making “me too” drugs of similar nature and capture smaller share of the market. Smaller companies, which cannot afford to have such gigantic R & D efforts have to be contended with obtaining license from the parent company to distribute the drug in developing countries under their brand name.
To make a novel drug, it is estimated that after testing about 30 -40,000 compounds, one compound qualifies for IND status. Out of 50 IND level compounds, one passes for NDA status, and out of 5-10 NDA level compounds only one enters the market as a drug !
We all can appreciate that it is almost impossible for the drug houses in India to undertake such gigantic effort to produce new and novel indigenous drugs. Our FDA is not strong enough to be the watch dogs in order to protect the rights and safety of a common man.
From all this discussion it would be clear why we have to import many drugs from abroad and pay hefty sums for our prescriptions.
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